<ns4:p><ns4:bold>Background</ns4:bold>: Depression is a risk factor for worse HIV outcomes in persons living with HIV/AIDS, including engagement-in-care, HIV medication adherence, and retention-in-care. Depression has a prevalence of more than three times as high as in the general population. Despite this, there are few randomized studies of antidepressants in HIV-infected Africans, including those with opportunistic infections.</ns4:p><ns4:p> <ns4:bold>Methods: </ns4:bold>We enrolled 460 HIV-infected Ugandans with cryptococcal meningitis into a randomized clinical trial of adjunctive sertraline vs placebo (2015-2017). We defined depression using the Center for Epidemiologic Studies Depression Scale (CES-D) score of &gt;15, and severe depression as &gt;26 at one and three months after meningitis diagnosis and initiation of treatment. We evaluated the relationship between sertraline and depression, as well as associations with persistent depression, at three months.</ns4:p><ns4:p> <ns4:bold>Results: </ns4:bold>At one- and three-months post meningitis diagnosis, 62% (108/174) and 44% (74/169) of all subjects had depression (CES&gt;15), respectively. At three months, sertraline-treated subjects had consistent risk for depression as placebo-treated subjects but were significantly less likely to have severe depression (CES&gt;26) (OR 0.335; 95%CI, 0.130-0.865). Of those with depression at one month, sertraline-treated subjects were less likely than placebo-treated subjects to be depressed at three months (p=0.05). Sertraline was the only factor we found significant in predicting persistent depression at three months among those with depression at one month.</ns4:p><ns4:p> <ns4:bold>Conclusions: </ns4:bold>Depression is highly prevalent in HIV-infected persons who have survived cryptococcal meningitis. We found that sertraline is associated with a modest reduction in depression in those with depression at baseline and a significant decrease in severe depression.</ns4:p>