A first-of-its-kind comparison between elite pro athletes suggests higher overall mortality among NFL players compared with MLB players. NFL players also appear to have higher risk of dying from cardiovascular and neurodegenerative causes compared with MLB peers. The differences warrant further study of sport-specific mechanisms of disease development. Clinicians treating current and former NFL players should be vigilant about the presence of cardiovascular and neurologic symptoms and promptly treat risk factors such as sleep apnea, obesity, hypertension.