Background and Aims: An important but much less researched burden of human immunodeficiency virus (HIV) in Sub-Saharan Africa includes the associated mental health outcomes of living with the virus. This study aimed to estimate the prevalence of depression, anxiety, and stress, and describe some of the socio-demographic associations among people living with HIV (PLHIV) in Ghana. Methods: A cross-sectional study was conducted at the Cape Coast Teaching Hospital, Ghana. Simple random sampling was used to recruit 395 PLHIV who access HIV-related services at the antiretroviral therapy clinic. The Depression, Anxiety, and Stress Scale-21 was used to assess prevalence of depression, anxiety, and stress. Frequencies and percentages were used to estimate the prevalence and multivariable logistic regression was used to evaluate sociodemographic factors associated with depression, anxiety, and stress. Results: The prevalence estimates of depression, anxiety, and stress among PLHIV were 28.6% (95% confidence interval [CI] 24.4–33.3), 40.8% (95% CI = 36.0–45.8), and 10.6% (95% CI = 7.9–14.1), respectively. Females reported higher prevalence of depression (32.2%; 95% CI = 27.2–37.7), anxiety (44.0%; 95% CI = 38.4–49.6), and stress (12.6%; 95% CI = 9.4–17.0) compared to depression (17.5%; 95% CI = 11.1–26.4), anxiety (30.9%; 95% CI = 22.5–40.7), and stress (4.1%; 95% CI = 1.2–10.4) among males. PLHIV without a regular partner were about 0.63 increased odds of experiencing anxiety compared to those with a regular partner (AOR = 0.63, 95% CI = 0.40–1.00: p = 0.049). PLHIV without formal education were about 0.49 and 0.44 increased odds to experience anxiety and stress, respectively compared to those with tertiary education. Conclusions: Generally, the levels of stress, anxiety, and depression are high among PLHIV, but disproportionately higher among females. Mental health assessment and management should be integrated into the HIV care services. There should be capacity building for health care workers to offer differentiated service delivery based on mental health care needs of PLHIV.
