IMPORTANCE Psychiatric interventions offered after natural disasters commonly address subsyndromal symptom presentations, but often remain insufficient to reduce the burden of chronic posttraumatic stress disorder (PTSD). OBJECTIVE To simulate a comparison of a stepped care case-finding intervention (stepped care [SC]) vs a moderate-strength single-level intervention (usual care [UC]) on treatment effectiveness and incremental cost-effectiveness in the 2 years after a natural disaster. DESIGN, SETTING, AND PARTICIPANTS This study, which simulated treatment scenarios that start 4 weeks after landfall of Hurricane Sandy on October 29, 2012, and ending 2 years later, created a model of 2 642 713 simulated agents living in the areas of New York City affected by Hurricane Sandy. INTERVENTIONS Under SC, cases were referred to cognitive behavioral therapy, an evidence-based therapy that aims to improve symptoms through problem solving and by changing thoughts and behaviors; noncases were referred to Skills for Psychological Recovery, an evidence-informed therapy that aims to reduce distress and improve coping and functioning. Under UC, all patients were referred only to Skills for Psychological Recovery. MAIN OUTCOMES AND MEASURES The reach of SC compared with UC for 2 years, the 2-year reduction in prevalence of PTSD among the full population, the 2-year reduction in the proportion of PTSD cases among initial cases, and 10-year incremental cost-effectiveness. RESULTS This population of 2 642 713 simulated agents was initialized with a PTSD prevalence of 4.38%(115 751 cases) and distributions of sex (52.6%female and 47.4%male) and age (33.9%aged 18-34 years, 49.0%aged 35-64 years, and 17.1%aged-65 years) that were comparable with population estimates in the areas of New York City affected by Hurricane Sandy. Stepped care was associated with greater reach and was superior to UC in reducing the prevalence of PTSD in the full population: Absolute benefit was clear at 6 months (risk difference [RD],-0.004; 95%CI,-0.004 to-0.004), improving through 1.25 years (RD,-0.015; 95%CI,-0.015 to-0.014). Relative benefits of SC were clear at 6 months (risk ratio, 0.905; 95%CI, 0.898-0.913), with continued gains through 1.75 years (risk ratio, 0.615; 95%CI, 0.609-0.662). The absolute benefit of SC among cases was much stronger, emerging at 3 months (RD,-0.006; 95%CI,-0.007 to-0.005) and increasing through 1.5 years (RD,-0.338; 95%CI,-0.342 to-0.335). Relative benefits of SC among cases were equivalent to those observed in the full population. The incremental cost-effectiveness of SC compared with UC was $3428.71 to $6857.68 per disability-adjusted life year avoided, and $0.80 to $1.61 per PTSD-free day. CONCLUSIONS AND RELEVANCE The results of this simulation study suggest that SC for individuals with PTSD in the aftermath of a natural disaster is associated with greater reach than UC, more effectiveness than UC, and is well within the range of acceptability for cost-effectiveness. Results should be considered in light of limitations inherent to agent-based models.