Few studies have evaluated age and racial/ethnic differences in the prevalence of symptoms in human immunodeficiency virus (HIV)-infected persons. Thus, the objective of this study was to compare the prevalence of gastrointestinal, metabolic, general malaise, neurologic, or other self-reported symptoms by age and race/ethnicity among 1574 HIV-infected women enrolled in the Women's Interagency HIV Study and 955 HIV-infected men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study. All patients had known dates of initiation of highly active antiretroviral therapy. It was observed that women aged 50 years or more were less likely to experience gastrointestinal symptoms (24% vs. 27%; multivariable P=0.024), but more likely to experience general malaise (47% vs. 37%; multivariable P=0.004), neurologic (44% vs. 38%; multivariable P=0.048), or other symptoms (40% vs. 28%; multivariable P<0.001) compared with women less than 40 years of age. Only neurologic symptoms had a higher prevalence among older MSM (52% vs. 37%; multivariable P=0.002), largely driven by paresthesias (48% vs. 31%; multivariable P=0.004), the most common individual symptom reported by men. Caucasian women generally had the highest prevalence of symptoms, and African American women had the lowest prevalence. Few racial/ethnic differences were noted for MSM. Depression and a prior diagnosis of acquired immunodeficiency syndrome were the strongest and most consistent predictors of clinical symptoms in both cohorts. In summary, the prevalence of reported symptoms varies with patient race/ethnicity, age, and modifiable factors, such as depression and HIV disease stage. Clinicians should consider these factors when counseling patients regarding potential adverse effects of antiretrovirals or symptoms associated with HIV disease.