We assessed whether directly observed fluoxetine treatment reduced depression symptom severity and improved HIV outcomes among homeless and marginally housed HIV-positive adults in San Francisco, California, from 2002 to 2008.We conducted a nonblinded, randomized controlled trial of once-weekly fluoxetine, directly observed for 24 weeks, then self-administered for 12 weeks (n = 137 persons with major or minor depressive disorder or dysthymia). Hamilton Depression Rating Scale score was the primary outcome. Response was a 50% reduction from baseline and remission a score below 8. Secondary measures were Beck Depression Inventory-II (BDI-II) score, antiretroviral uptake, antiretroviral adherence (measured by unannounced pill count), and HIV-1 RNA viral suppression (< 50 copies/mL).The intervention reduced depression symptom severity (b = -1.97; 95% confidence interval [CI] = -0.85, -3.08; P < .001) and increased response (adjusted odds ratio [AOR] = 2.40; 95% CI = 1.86, 3.10; P < .001) and remission (AOR = 2.97; 95% CI = 1.29, 3.87; P < .001). BDI-II results were similar. We observed no statistically significant differences in secondary HIV outcomes.Directly observed fluoxetine may be an effective depression treatment strategy for HIV-positive homeless and marginally housed adults, a vulnerable population with multiple barriers to adherence.