The issue of whether optimism may prospectively protect against disease progression is one that has generated much interest, with mixed results in the literature. The purpose of this study was to determine whether dispositional optimism predicts slower disease progression in HIV. Two indicators of disease progression, CD4 counts and viral load, were assessed over 2 years in a diverse group (men, women, White, African American, Hispanic) of 177 people with HIV in the midrange of disease at entry to the study. Optimism predicted slower disease progression (less decrease in CD4 and less increase in viral load) controlling for baseline CD4 and viral load, antiretroviral treatment, gender, race, education, and drug use. Those low on optimism (25th percentile) lost CD4 cells at a rate 1.55 times faster than those high on optimism (75th percentile). Optimists had higher proactive behavior, less avoidant coping, and less depression: These variables mediated the linear optimism-disease progression relationship. Thus, optimists may reap health benefits partly through behavioral (proactive behavior), cognitive (avoidant coping), and affective (depression) pathways. Implications, limitations, and interpretations are discussed.