The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date. Author summary: Although lifelong HIV antiretroviral therapy (ART) suppresses virus, the major barrier to an HIV cure is the persistence of infected cells, "the HIV reservoir." There are limited host genomic HIV reservoir studies to date. We performed a large cross-sectional study of 191 people with HIV on ART and measured the HIV reservoir size and host gene expression (RNA-seq) from blood CD4+ T cells. We found that individuals with higher expression of host genes involved in suppressing cell proliferation (P3H3, NBL1) had a smaller total HIV reservoir size. We also observed that individuals with more "transcriptionally active" HIV reservoir had decreased expression of inflammatory signaling (e.g., IL-1β, TLR7, TNF-α, IL-10) genes as well as two membrane channel proteins (encoded by KCNJ2, GJB2). While we were able to validate some of these findings at the protein level (P3H3, IL-10, TNF-α), further studies are needed to confirm these findings in larger cohorts with longitudinal sampling, including traditionally underrepresented populations in HIV cure research. [ABSTRACT FROM AUTHOR]