Elevated neuroticism may confer vulnerability to the depressogenic effects of stressful life events (SLEs). However, the mechanisms underlying this susceptibility remain poorly understood. Accumulating evidence suggests that stress-related disruptions in neural reward processing might undergird links between stress and depression. Using data from the Saint Louis Personality and Aging Network (SPAN) study and Duke Neurogenetics Study (DNS), we examined whether neuroticism moderates links between stressful life events (SLE) and depression as well as SLEs and ventral striatum (VS) response to reward. In the longitudinal SPAN sample (n = 971 older adults), SLEs prospectively predicted future depressive symptoms, especially among those reporting elevated neuroticism, even after accounting for prior depressive symptoms and previous SLE exposure (NxSLE interaction: p = .016, ΔR² = 0.003). Cross-sectional analyses of the DNS, a young adult college sample with neuroimaging data, replicated this interaction (n = 1,343: NxSLE interaction: p = .019, ΔR² = 0.003) and provided evidence that neuroticism moderates the association between SLEs and reward-related VS response (n = 1,195, NxSLE: p = .017, ΔR² = 0.0048). Blunted left VS response to reward was associated with a lifetime depression diagnosis, r = -0.07, p = .02, but not current depressive symptoms, r = -0.003, p = .93. These data suggest that neuroticism may promote vulnerability to stress-related depression and that sensitivity to stress-related reductions in VS response may be a potential neural mechanism underlying vulnerability to clinically significant depression. (PsycInfo Database Record (c) 2021 APA, all rights reserved).