Previously we demonstrated that chronic Δ9‐tetrahydrocannabinol (THC) administration attenuates classic markers of simian immunodeficiency virus (SIV) disease progression, decreases early mortality and attenuates inflammation in SIV‐infected rhesus macaques. The mechanisms involved in amelioration of disease progression are unknown. The gut is an important target for HIV/SIV infection. We hypothesized that modulation of genes involved in mucosal immunity, viral replication and barrier function may contribute to THC‐modulated disease progression. We examined the impact of chronic THC administration on the duodenal transcriptome. Using GeneGO, duodenal gene expression of vehicle‐ or THC‐administered SIV‐infected (THC/SIV) macaques was compared to uninfected naive macaques. Analysis of the 188 genes differentially regulated by THC using STRING database identified their role in antiviral and stress responses and gut barrier and immune function. THC/SIV gene expression ≥ 1.5‐fold or ≤ 0.5‐fold was verified by RT‐qPCR and Western blot. THC significantly increased mRNA expression of antiviral MX‐1, protein expression of IFIT1 and HSPA2 and attenuated the increase of IGJ protein. These results suggest that THC‐mediated changes in gut gene expression may contribute to functional modification of gut immunity and participate in modulation of disease progression. Supported by DA020419, DA030053