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Diagnosis of neurobehavioral syndromes associated with HIV infection requires the determination that neuropsychological (NP) deficits are present, are not caused by any comorbid (e.g., psychiatric) condition, and significantly affect everyday functioning. Methamphetamine (Meth) dependence and depression are common comorbid conditions with HIV and may complicate diagnosis of HIV-associated neurobehavioral syndromes. The current study examined the complex relationships between depression and NP impairment, and self-report of problems with everyday functioning, in 362 adults with HIV infection or Meth dependence, or both. Everyday functioning was measured with questionnaires of instrumental activities of daily living (IADLs) and reported cognitive difficulties. Results indicate that comorbid HIV and Meth did not increase the likelihood of complaints regarding everyday functioning, beyond what was seen with either single risk factor. Across all groups, depressive symptoms predicted greater IADL decline and cognitive complaints, while NP impairment predicted cognitive complaints more than IADL decline. Both IADL decline and cognitive complaints were associated with higher rates of unemployment and worse clinician ratings of overall functioning (Karnofsky ratings), even when depressive symptoms were controlled. These results suggest that depressive symptoms should not be used to dismiss subjective complaints related to everyday functioning even though depressive symptoms account for significant variance in self-reported complaints. Additional research is needed to clarify the potentially reciprocal causal relationships between depressive symptoms and impairment in everyday functioning.