HIV prevention fatigue (the sense that prevention messages are tiresome) and being overly optimistic about HIV treatments are hypothesized to increase HIV risk behavior. Little research has examined these constructs and their correlates among young men who have sex with men (YMSM), who are at high risk for HIV. YMSM (N = 352; Mage = 20; 50% Black) completed measures of prevention fatigue, treatment optimism, HIV risk behaviors, and HIV-related knowledge and attitudes during a longitudinal study. Overall, YMSM reported low levels of HIV prevention fatigue and treatment optimism. Path analysis (n = 307) indicated that greater prevention fatigue and treatment optimism predicted higher rates of condomless sex, but condomless sex did not predict later increases in prevention fatigue or treatment optimism. Results are inconsistent with the hypothesis of high prevention fatigue and treatment optimism among YMSM and point to potential causal relationships among these variables and condomless sex.