Objective: Altruism and cognitive reserve (CR) are associated with better health and well-being. We investigated the independent and moderator effects of altruism and CR on health and well-being in multiple sclerosis (MS). Methods: Secondary analysis of data (n = 859) from the North American Research Committee on MS registry. Outcomes: Performance Scales; Ryff Psychological Well-Being; Diener Life Satisfaction. Analyses: Hierarchical series of regression models adjusted for demographic covariates and stratified by neurologic disability. Hypotheses: Independent and moderator effects of altruism and CR on health and well-being. Results: Neither altruism nor passive CR had independent effects on functional health problems. Higher active CR was associated with fewer functional health problems. Altruism and active CR but not passive CR had significant main effects on well-being for all levels of disability. There were no moderator effects. Conclusions: Whereas altruism primarily impacted well-being active CR was an important predictor of both functional health and well-being.