Patient-centered measures of functioning and well-being are needed to monitor and improve health for HIV-infected persons. We estimated the associations between HRQOL and symptoms over time in HIV-infected persons, adjusting for demographic and clinical characteristics using a longitudinal study of a nationally representative cohort of 2267 patients in care for HIV infection surveyed in 1996 and again in 1998. We used two global measures of HRQOL (overall health and overall quality of life) scored to have a mean of 50 and standard deviation of 10 in the sample. The total number of symptoms decreased (-1.29, p<0.001 for the difference), and overall health (1.09, p<0.001 for the difference) and overall quality of life (1.31, p<0.001 for the difference) improved over the period. Controlling for baseline symptoms and HRQOL, each additional symptom at follow-up (B=-1.14, p<0.001) was associated with worsened overall health and worsened overall quality of life (B=-0.95, p<0.001). The association of two additional symptoms with lower global HRQOL was similar in magnitude to the effect of having significant depressive symptoms or the diagnosis of AIDS. In conclusion, among HIV-infected patients, symptoms are significantly related to HRQOL over time. The functioning and well-being of patients with HIV is inextricably linked to the symptoms they experience.