Numerous studies have documented the effects of personality on health outcomes. However, which traits are most relevant to health, and the precise magnitude of their effects, is inconsistent across studies. The present study used a large sample (N=460,172) to replicate and extend the relations between the Big Five and three health-related outcomes: self-reported health, body mass index, and substance use. Low Conscientiousness predicted all outcomes, indicating that individuals who are less responsible and less self-controlled tend to report poorer health, be more overweight, and engage in more substance use. In addition, individuals who were more emotionally unstable (high Neuroticism) reported poorer health, and individuals prone to seek out social experiences and rewards (high Extraversion) engaged in more frequent substance use.