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Highlights • Perceived vulnerability to COVID-19 (PVC) was positively related to COVID-19-related worries, social isolation, and traumatic stress (TS). • Both COVID-19-related worries and social isolation were significant mediators of the relationship between PVC and TS. • The indirect effect of PVC on TS through COVID-19-related worries was stronger for participants who reported greater social isolation. • Social isolation and disease-related worries may be important variables that can be targeted in interventions to reduce pandemic-related TS., The purpose of the present study was to propose and test two models to understand the relationship between perceived vulnerability to COVID-19 (PVC) and COVID-19-related traumatic stress (TS), as well as the variables that may mediate and moderate this relationship among individuals who have not yet been infected with COVID-19. Using an online survey, data were collected between late March and early April 2020. Participants were recruited through Amazon Mechanical Turk and included 747 adults living in the United States. Supporting our hypotheses, results indicated that both COVID-19-related worries and social isolation were significant mediators of the relationship between PVC and TS (Model 1). In addition, the results of a moderated mediation analysis indicated that the indirect effect of PVC on TS through COVID-19-related worries was stronger for participants who reported greater social isolation (Model 2). Although future research is needed, these findings suggest that both social isolation and disease-related worries may be important variables that can be targeted in interventions to reduce pandemic-related TS.