Research shows that optimism can positively impact health, but when and why people feel optimistic when confronting health challenges is less clear. Findings from six studies show that the frames people adopt when thinking about health challenges influence their optimism about overcoming those challenges, and that their culture moderates this effect. In cultures where the independent self is highly accessible, individuals adopting an initiator frame (how will I act, regardless of the situations I encounter?) were more optimistic than those adopting a responder frame (how will I react to the situations I encounter?); the converse occurred for individuals from cultures where the interdependent self is highly accessible. Moreover, mediation and moderation evidence revealed that this interactive effect of culture and frame on optimism was driven by people’s ability to easily imagine the recovery process. These effects held for distinct health challenges (cancer, diabetes, flood-related illness, traumatic injury) and across single-country and cross-country samples, as well as impacted positive health outcomes and decisions ranging from anticipated energy, physical endurance, and willingness to take on more challenging physical therapy to intentions to get vaccinated, stick to a doctor recommended diet, and undertake a physically strenuous vacation.