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Female sex, high estrogen levels, aging, obesity, and dyslipidemia are some of the risk factors associated with gallstone formation. HIV-infected patients on combination antiretroviral therapy (cART) are more prone to hypercholesterolemia. Bile acid synthesis is initiated by cholesterol 7-alpha hydroxylase (CYP7A1) and regulated by hepatocyte nuclear factors (HNF1α, HNF4α, and LXRb). The aim of this study was to evaluate the expression of HNF1α, HNF4α, LXRb, and miRNAs (HNF4α specific: miR-194-5p and miR-122^*_1) that regulate CYP7A1 transcription in HIV-infected Black South African women on cART and presenting with gallstones relative to HIV-negative patients with gallstone disease. Females (<i>n</i> = 96) presenting with gallstone disease were stratified based on HIV status. The gene expression of <i>CYP7A1</i>, <i>HNF1α</i>, <i>HNF4α</i>, <i>LXRb</i>, miR-194-5p, and miR-122^*_1 was determined using RT-qPCR. Messenger RNA and miRNA levels were reported as fold change expressed as 2^−ΔΔCt (RQ min; RQ max). Fold changes >2 and <0.5 were considered significant. HIV-infected females were older in age (<i>p</i> = 0.0267) and displayed higher low-density lipoprotein cholesterol (LDL-c) (<i>p</i> = 0.0419), <i>CYP7A1</i> [2.078-fold (RQ min: 1.278; RQ max: 3.381)], <i>LXRb</i> [2.595-fold (RQ min: 2.001; RQ max: 3.000)], and <i>HNF1α</i> [3.428 (RQ min: 1.806; RQ max: 6.507] levels. <i>HNF4α</i> [0.642-fold (RQ min: 0.266; RQ max: 1.55)], miR-194-5p [0.527-fold (RQ min: 0.37; RQ max: 0.752)], and miR-122*_1 [0.595-fold (RQ min: 0.332; RQ max: 1.066)] levels were lower in HIV-infected females. In conclusion, HIV-infected women with gallstone disease displayed higher LDL-c levels and increased bile acid synthesis, which was evidenced by the elevated expression of CYP7A1, HNF1α, and LXRb. This could have been further influenced by cART and aging.