BACKGROUND: In 2005, the Food and Drug Administration placed a black-box warning (the most stringent warning for drugs) on all nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) stating that these agents may cause heart attacks and/or strokes. No level I evidence demonstrates that nonselective NSAIDs increase cardiovascular risk. An alternative hypothesis is that hip and knee osteoarthritis (OA) indirectly causes cardiovascular disease (CVD) through decreased activity and NSAIDs are correlated with CVD as an arthritis treatment. METHODS: Systematic reviews were conducted to find observational studies evaluating the association of hip and/or knee OA, CVD, activity, walking, and step counts. The systematic review found studies correlating hip and/or knee OA and CVD morbidity incidence (n = 2); CVD morbidity prevalence (n = 6); odds ratios, relative risks, or hazard ratios of CVD morbidity (n = 11); relative risk, standardized mortality ratios, or hazard ratios of CVD mortality (n = 14); and all-cause mortality hazard ratios associated with NSAID use (n = 3). RESULTS: Hip OA (5 studies), knee OA (9 studies), and hip and knee OA (6 studies) are linked to an increased risk of CVD morbidity and mortality. Cardiac risk increases with validated disability scores, use of walking aids, walking difficulties, longer follow-up times, younger ages of OA onset, numbers of joints involved, and OA severities. No study linked NSAID use to cardiac disease. CONCLUSIONS: All studies with more than 10-year follow-up linked cardiac disease with hip and knee OA. No study linked nonselective NSAID use to CVD. The Food and Drug Administration should reconsider the black-box warnings on naproxen, ibuprofen, and celecoxib.