The main objective of this study was to use structural equation modeling (SEM) to clarify the relationship between subjective cognitive complaints and neuropsychological functioning in 160 adults with HIV infection. Participants completed questionnaires assessing cognitive complaints, symptoms of depression, and HIV-related medical symptoms. Neuropsychological tests included measures of attention, verbal fluency, psychomotor skills, learning, memory, and executive skills. SEM was used to test models of the relationships among cognitive complaints, mood, and medical symptoms with neuropsychological functioning. The model indicated that although depressed mood (beta = 0.32, p < .01) and medical symptoms (beta = 0.31, p < .01) influenced cognitive complaints, cognitive complaints were independently associated with poorer neuropsychological performance (beta = 0.39, p < .01). Mood and medical symptoms were significantly correlated but were not significantly associated with neuropsychological skills.