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Background: Human immunodeficiency virus and injection substance use have an influence on genes and gene expression. These effects could be beneficial or detrimental in defining disease outcomes. Adiponectin gene is key in modulating metabolic and immunoregulatory functions. Understanding the effects of human immunodeficiency virus and injection substance use on the gene in the context of antiretroviral therapy is important for predicting disease outcomes., Methods: This cross-sectional genetic study determined polymorphisms in the promoter region of adiponectin gene. Two variants were analyzed: rs2241766 and rs266729. Polymorphisms were associated with clinical markers of disease outcome; underweight, immunosuppression and viral suppression. The variants were genotyped via random fragment length polymorphism., Result: GC haplotype was associated with higher odds of having underweight (OR, 2.21; 95% CI, 1.83-4.60; P=0.008 vs. OR, 2.30; 95% CI, 1.89-4.71; P=0.006) in antiretroviral treatment - naive and experienced injection substance users and immunosuppression (OR, 1.90; 95% CI 1.67-3.98, P=0.041) in naive. Bonferroni correction revealed GC haplotype carriers only to have low body mass index in both naive (median, 14.8; IQR, 3.2 kg/m 2 ; P=0.002) and experienced (median, 15.2; IQR, 3.2 kg/m 2 ; P=0.002) injection substance users. Circulating total adiponectin levels were higher in naive (median, 19.5; IQR, 7.9 µg/ml) than - experienced (median, 12.0; IQR, 4.4 µg/ml) injection substance users (P=0.0001). GC carriers presented with low serum adiponectin levels in both study groups., Conclusion: The study revealed haplotypes of adiponectin gene at loci rs2241766 and rs266729 that could determine disease outcomes in human immunodeficiency virus -1 antiretroviral treatment- naive and experienced injection substance users., (Copyright: © 2020 Shaviya N. et al.)