Abstract Psychological distress and biobehavioral vulnerability (e.g., arising from being older or sedentary) have independently predicted immune responses to influenza vaccination in older adults. Recent research examining basal inflammatory markers suggests that, rather than having additive effects, distress and vulnerability interact with each other. The present study tested the interactions between distress and age, sex, education, BMI, sleep quality, and physical activity over up to 8years in older adults (N=134; M age=74years) who received annual influenza vaccinations. Measured vaccination responses were changes from baseline in antibody to the three vaccine components, interleukin (IL)-6, and β2-microglobulin. As predicted, the most robust effects were interactions between distress and vulnerability. BMI interacted with stable individual differences in distress to predict antibody response (t(132)=3.09, p<0.003), such that only the combination of low BMI and low distress was associated with a more robust antibody response. Likewise, changes in physical activity over time interacted with changes in distress (t(156)=2.96, p<0.004), such that only the combination of increased physical activity and decreased distress was associated with a more robust antibody response. Finally, there was a smaller tendency for age to interact with stable individual differences in distress (t(130)=2.46, p<0.015), such that distress was more strongly associated with post-vaccination IL-6 at older ages. The synergistic effects of distress and other forms of vulnerability are an important direction for future research and a target for interventions to improve immunological health in older adults.