<p>HIV majorly contributes to the disease burden in South Africa. Depressive symptoms are common in people living with HIV (PLHIV). Few studies compared depressive symptoms between PLHIV and those without HIV. The aim of the study was to examine the association of HIV status and depressive symptoms. Moreover, the study aimed to explore the comparison between HIV-negative participants and the different HIV-positive sub-groups regarding their depressive symptoms. A cross-sectional analysis was conducted among PLHIV and HIV-negative participants in rural South Africa, using the baseline data of the Ndlovu Cohort study. Data was collected on demographics, socioeconomic status, and depressive symptoms using the PHQ-9 questionnaire. A score of 10 and above indicated depressive symptoms. Logistic regression analysis on the relationship between HIV status and depressive symptoms was used while adjusting for age, sex, level of education, employment status, income, and ever smoking. The study included 1,927 participants; 46% were PLHIV and 239 (12.5%) had depressive symptoms. PLHIV were more likely to have depressive symptoms than HIV-negative participants (OR 1.34, 95% CI 1.01–1.77). This association was not statistically significant after adjusting for confounders (OR 1.22, 95% CI 0.92–1.63). Compared to HIV-negative participants, ART (antiretroviral treatment) naïve participants had statistically significant higher odds of depressive symptoms (OR 1.84, 95% CI 1.20–2.78). This association remained after adjusting for confounders (OR 1.72, 95% CI 1.11–2.61). There was no statistically significant difference in depressive symptoms between HIV-negative participants and those on ART, regardless of treatment regimen. In general, higher odds of depressive symptoms in ART-naïve PLHIV could reflect poor coping with diagnosis of HIV. Future research to investigate the relation between ART regimen and depressive symptoms, to establish causality and to identify changes over time, is warranted.</p>