The objective of this population-based retrospective cohort study was to identify factors associated with lifespan in pet dogs evaluated at primary care veterinary hospitals. Dogs ≥3 mo of age that visited any of 787 US hospitals at least twice from January 1, 2010, through December 31, 2012, were included. Survival curves were constructed for dogs by reproductive status, breed, body size, and purebreed (versus mixed-breed) status. Multivariate Cox proportional hazard regression was performed to identify factors associated with lifespan. There were 2,370,078 dogs included in the study, of whom 179,466 (7.6%) died during the study period. Mixed-breed dogs lived significantly longer than purebred dogs, and this difference was more pronounced as body size increased. Controlling for other factors, dogs of either sex had a greater hazard of death over the study follow-up period if sexually intact rather than gonadectomized. For dogs who lived to 2 yr of age, the hazard of death decreased with increasing frequency of dental scaling. Our findings support previous reports of the impact of body size and gonadectomy on lifespan and provide new evidence in support of ultrasonic dental scaling and mixed breeding.