Background:　Working　memory　refers　to　a　process　of　temporary　storage　and　manipulation　of　information　to　support　planning,　decision-making,　and　action.　Frequently　comorbid　alcohol　misuse　and　sleep　deficiency　have　both　been　associated　with　working　memory　deficits.　However,　how　alcohol　misuse　and　sleep　deficiency　interact　to　impact　working　memory　remains　unclear.　In　this　study,　we　aim　to　investigate　the　neural　processes　inter-relating　alcohol　misuse,　sleep　deficiency　and　working　memory.　Methods:　We　curated　the　Human　Connectome　Project　(HCP)　dataset　and　investigated　the　neural　correlation　of　working　memory　in　link　with　alcohol　use　severity　and　sleep　deficiency　in　991　young　adults　(521　women).　The　two　were　indexed　by　the　first　principal　component　(PC1)　of　principal　component　analysis　of　all　drinking　metrics　and　Pittsburgh　Sleep　Quality　Index　(PSQI)　score,　respectively.　We　processed　the　imaging　data　with　published　routines　and　evaluated　the　results　with　a　corrected　threshold.　We　used　path　model　to　characterize　the　inter-relationship　between　the　clinical,　behavioral,　and　neural　measures,　and　explored　sex　differences　in　the　findings.　Results:　In　whole-brain　regression,　we　identified　β　estimates　of　dorsolateral　prefrontal　cortex　response　(DLPFC　β)　to　2-　vs.　0-back　in　correlation　with　PC1.　The　DLPFC　showed　higher　activation　in　positive　correlation　with　PC1　across　men　and　women　(r=0.16,　P＜0.001).　Path　analyses　showed　the　model　PC1　→　DLPFC　β　→　differences　in　reaction　time　(2-　minus　0-back;　RT2-0)　of　correct　trials　→　differences　in　critical　success　index　(2-　minus　0-back;　CSI2-0)　with　the　best　fit.　In　women　alone,　in　addition　to　the　DLPFC,　a　cluster　in　the　superior　colliculus　(SC)　showed　a　significant　negative　correlation　with　the　PSQI　score　(r=-0.23,　P＜0.001),　and　the　path　model　showed　the　inter-relationship　of　PC1,　PSQI　score,　DLPFC　and　SC　β＇s,　and　CSI2-0in　women.　Conclusions:　Alcohol　misuse　may　involve　higher　DLPFC　activation　in　functional　compensation,　whereas,　in　women　only,　sleep　deficiency　affects　2-back　memory　by　depressing　SC　activity.　In　women　only,　path　model　suggests　inter-related　impact　of　drinking　severity　and　sleep　deficiency　on　2-back　memory.　These　findings　suggest　potential　sex　differences　in　the　impact　of　drinking　and　sleep　problems　on　working　memory　that　need　to　be　further　investigated.　©　2024　AME　Publishing　Company.　All　rights　reserved.