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Recent research suggests that the presence of posttraumatic stress disorder (PTSD) and depressive symptoms is independently related to abnormal hormone levels, inadequate medication adherence, and faster HIV disease progression. Although PTSD and depression occur comorbidly at high rates, the impact of both disorders on adherence and disease progression has not been examined. The present study examined the impact of PTSD and comorbid depression on CD4 cell counts and medication adherence in 58 male and 11 female (36% African American) HIV-positive individuals recruited from an AIDS service organization. Results revealed that participants high in depressive symptoms had lower CD4 cell counts and were less likely to adhere to their medication regimens than participants high in PTSD symptoms and those high in comorbid symptomatology. The present results suggest that the presence of depressive symptoms may be responsible for the observed impact of PTSD on people living with HIV (PLWH), and that failure to examine comorbid disorders may not adequately address the impact of clinical symptoms on people living with HIV.