OBJECTIVES Many studies have assessed quality of life in patients with HIV, but information regarding patients' perceptions of life pre- vs. post-HIV diagnosis is scarce. Our objective was to assess longitudinally how patients with HIV compare their quality of life currently vs. prior to their HIV diagnosis. METHODS We interviewed and reviewed the medical records of 347 outpatients with HIV from 3 cities in the US. In 2 interviews 12-18 months apart, patients compared their life now with their life before HIV was diagnosed. Covariates included demographic and clinical characteristics; HIV-specific health status, symptoms, and concerns; spirituality/religion; lifestyle; social support; self-perception; and optimism. RESULTS The patients' mean (SD) age was 44.8 (8.3) years; half were minorities; and 269 (78%) were taking antiretroviral therapy. Comparing life at time 1 vs. before diagnosis, 109 (31%) patients said their life was better at time 1, 98 (28%) said it was worse, and the rest said it was about the same or didn't know. By time 2, approximately one-fifth of the patients changed their answers to favor life improvement and one-sixth changed them to favor life deterioration. In multivariable analysis, change in perception for the better between time 1 and time 2 (vs. pre-diagnosis) was positively associated with change in level of spirituality and with time 1 positive religious coping scores (C-statistic = 0.67). CONCLUSIONS A substantial minority of patients with HIV feel that their life is better than it was before their diagnosis, although results of such comparisons often change over time.