diff --git a/src/main/scala/com/fulcrumgenomics/fastq/DemuxFastqs.scala b/src/main/scala/com/fulcrumgenomics/fastq/DemuxFastqs.scala
index cb5d936f3..7733d69ac 100644
--- a/src/main/scala/com/fulcrumgenomics/fastq/DemuxFastqs.scala
+++ b/src/main/scala/com/fulcrumgenomics/fastq/DemuxFastqs.scala
@@ -29,6 +29,7 @@ import com.fulcrumgenomics.FgBioDef._
 import com.fulcrumgenomics.bam.api.{SamOrder, SamRecord, SamWriter}
 import com.fulcrumgenomics.cmdline.{ClpGroups, FgBioTool}
 import com.fulcrumgenomics.commons.CommonsDef.{DirPath, FilePath, PathPrefix, PathToFastq}
+import com.fulcrumgenomics.commons.collection.LeastRecentlyUsedCache
 import com.fulcrumgenomics.commons.io.PathUtil
 import com.fulcrumgenomics.commons.util.{LazyLogging, Logger}
 import com.fulcrumgenomics.fastq.FastqDemultiplexer.{DemuxRecord, DemuxResult}
@@ -45,6 +46,7 @@ import htsjdk.samtools.util.{Iso8601Date, SequenceUtil}
 
 import java.io.Closeable
 import java.util.concurrent.ForkJoinPool
+import scala.collection.immutable.ArraySeq
 import scala.collection.mutable.ListBuffer
 
 object DemuxFastqs {
@@ -379,6 +381,7 @@ class DemuxFastqs
  @arg(doc="Do not keep reads identified as control if true, otherwise keep all reads. Control reads are determined from the comment in the FASTQ header.")
  val omitControlReads: Boolean = false,
  @arg(doc="Mask bases with a quality score below the specified threshold as Ns") val maskBasesBelowQuality: Int = 0,
+ @arg(doc="The number of barcodes to cache; zero will disable the cache.") val cacheSize: Int = 1000000
 ) extends FgBioTool with LazyLogging {
 
   // Support the deprecated --illumina-standards option
@@ -468,7 +471,8 @@ class DemuxFastqs
       includeOriginal  = this.includeAllBasesInFastqs,
       fastqStandards   = this.fastqStandards,
       omitFailingReads = this.omitFailingReads,
-      omitControlReads = this.omitControlReads
+      omitControlReads = this.omitControlReads,
+      cacheSize        = this.cacheSize
     )
 
     val progress = ProgressLogger(this.logger, unit=1e6.toInt)
@@ -763,6 +767,7 @@ private[fastq] object FastqDemultiplexer {
   *                        and skipped bases.
   * @param omitFailingReads true if to remove reads that don't pass QC, marked as 'N' in the header comment
   * @param omitControlReads false if to keep reads that are marked as internal control reads in the header comment.
+  * @param cacheSize the number of barcodes to cache; zero will disable the cache.
   */
 private class FastqDemultiplexer(val sampleInfos: Seq[SampleInfo],
                                  readStructures: Seq[ReadStructure],
@@ -773,7 +778,8 @@ private class FastqDemultiplexer(val sampleInfos: Seq[SampleInfo],
                                  val maxNoCalls: Int = 2,
                                  val includeOriginal: Boolean = false,
                                  val omitFailingReads: Boolean = false,
-                                 val omitControlReads: Boolean = false) {
+                                 val omitControlReads: Boolean = false,
+                                 val cacheSize: Int = 0) extends LazyLogging {
   import FastqDemultiplexer._
 
   require(readStructures.nonEmpty, "No read structures were given")
@@ -787,6 +793,11 @@ private class FastqDemultiplexer(val sampleInfos: Seq[SampleInfo],
   private val sampleInfosNoUnmatched = sampleInfos.filterNot(_.isUnmatched)
   private val unmatchedSample        = sampleInfos.find(_.isUnmatched).getOrElse(throw new IllegalArgumentException("No unmatched sample provided."))
 
+  private val cache = if (this.cacheSize == 0) None else {
+    logger.info(f"Using cache of size: $cacheSize")
+    Some(new LeastRecentlyUsedCache[ArraySeq[Byte], (SampleInfo, Int)](maxEntries=cacheSize))
+  }
+
   /** The number of reads that are expected to be given to the [[demultiplex()]] method. */
   def expectedNumberOfReads: Int = this.variableReadStructures.length
 
@@ -802,7 +813,20 @@ private class FastqDemultiplexer(val sampleInfos: Seq[SampleInfo],
     * found, the unmatched sample and [[Int.MaxValue]] are returned. */
   private def matchSampleBarcode(subReads: Seq[SubRead]): (SampleInfo, Int) = {
     val observedBarcode = subReads.filter(_.kind == SegmentType.SampleBarcode).map(_.bases).mkString.getBytes
-    val numNoCalls      = observedBarcode.count(base => SequenceUtil.isNoCall(base))
+    cache match {
+      case None => matchSampleBarcode(observedBarcode=observedBarcode)
+      case Some(_cache) =>
+        val key = new ArraySeq.ofByte(observedBarcode)
+        _cache.get(key).getOrElse {
+          val result = matchSampleBarcode(observedBarcode=observedBarcode)
+          _cache.put(key, result)
+          result
+        }
+    }
+  }
+
+  private def matchSampleBarcode(observedBarcode: Array[Byte]): (SampleInfo, Int) = {
+    val numNoCalls = observedBarcode.count(base => SequenceUtil.isNoCall(base))
 
     // Get the best and second best sample barcode matches.
     val (bestSampleInfo, bestMismatches, secondBestMismatches) = if (numNoCalls <= maxNoCalls) {