Objectives Osteoarthritis (OA) is a leading cause of disability, but the relationship with premature mortality remains uncertain. We aimed to investigate the relationship between OA and mortality from any cause and from cardiovascular disease (CVD). Methods Electronic literature databases searches were conducted to identify prospective studies comparing mortality in a sample of people with and without OA. Risk of all-cause and CVD mortality were summarized using adjusted hazard ratios (HRs) for joint specific (hand, hip, and knee) and joint non-specific OA. New data from the Progetto Veneto Anziani (PRO.V.A.) study were also included. Results From the PRO.V.A. study (N = 2927), there was no significant increase in mortality risk for participants with any joint OA (N = 1858) compared to non-OA (all-cause, HR = 0.95, 95% CI: 0.77–1.15 and CVD, HR = 1.12, 95% CI: 0.82–1.54). On meta-analysis, seven studies (OA = 10,018/non-OA = 18,541), with a median 12-year follow-up, reported no increased risk of any-cause mortality in those with OA (HR = 1.10, 95% CI: 0.97–1.25). After removing data on hand OA, a significant association between OA and mortality was observed (HR = 1.18, 95% CI: 1.08–1.28). There was a significant higher risk of overall mortality for (1) studies conducted in Europe, (2) patients with multi-joint OA; and (3) a radiological diagnosis of OA. OA was associated with significantly higher CVD mortality (HR = 1.21, 95% CI: 1.10–1.34). Conclusions People with OA are at increased risk of death due to CVD. The relationship with overall mortality is less clear and may be moderated by the presence of hand OA. © 2016 Elsevier Inc.