To examine how exposure to direct-to-consumer advertising (DTCA) is associated with individuals’ engagement in prescription drug-related decision making. Based on the availability-heuristics perspective as a theoretical framework, we hypothesized that exposure to DTCA might improve individuals’ perceived susceptibility of diseases, thereby enhancing their engagement in prescription drug decision making. We considered optimistic bias (OB), a tendency of people’s underestimating their own risk for diseases compared with others’ risk, to be an effect modifier of the association between exposure to DTCA and perceived susceptibility. Data were collected by surveying the US adults aged 18 or older using an online survey platform. To test our hypotheses, we employed multivariate regressions by controlling for a number of covariates. A total of 327 responses were collected for our analyses. Respondents’ mean age was 38.5 years (SD = 12.8) and about half of them (48.9%) were females. As expected, we found that exposure to DTCA was significantly associated with individuals’ prescription decision engagement behaviors through their perceived susceptibility (regression coefficient (b)=0.030, 95% CI: 0.003-0.057). The association between DTCA exposure and their prescription decision engagement was mediated through perceived susceptibility. Of note, this association mediated by perceived susceptibility was modified by OB. The mediating effect of perceived susceptibility on the association was prominent among individuals with high OB (b=0.048, 95% CI: 0.007-0.089), but this effect was insignificant among those with low OB (b=0.003, 95% CI: -0.012, 0.030). Our findings align with the availability-heuristics perspective by supporting the association between DTCA exposure and individuals’ prescription decision engagement behaviors through their perceived susceptibility of diseases among those with higher optimistic bias. This study provides a new theoretical framework to understand the pathway between DTCA exposure and individuals’ prescription decision engagement behaviors.