Although optimism is usually conceptualized as a buffer against stressor-related changes in the immune system, some contradictory findings have emerged. The present research proposed that when facing conflicting goals, optimists are more likely to remain engaged with both goals and to experience higher short-term stress as a consequence. Optimists were therefore predicted to fare worse than pessimists immunologically when facing academic-social goal conflict but to fare better when not facing goal conflict. In the Study 1 sample (n = 48), optimism was associated with higher numbers of CD4+ cells among first-year law students who were less likely to have academic-social conflict and with lower numbers of CD4+ cells at midsemester among students who were more likely to have conflict. The results replicated in the Study 2 sample of law students (n = 22) using delayed-type hypersensitivity testing. Optimists may be subject to short-term physiological costs in their persistence to gain long-term rewards.