Arthritis is the leading cause of disability in the United States. Osteoarthritis, the most common form of arthritis, is a degenerative joint disease affecting both whites and African Americans similarly. African Americans have a high incidence rate of comorbidities, including hypertension, cardiovascular disease (CVD) risk factors and diabetes. Treatment of osteoarthritic pain in patients with comorbidities is often complicated by potential safety concerns. Traditional nonsteroidal antiinflammatory drugs (NSAIDs) and cyclooxygenase 2 (COX-2) specific NSAIDs have been shown to increase blood pressure in hypertensive patients taking antihypertensive medications. Patients with CVD risk factors taking low-dose aspirin for secondary prevention may be at increased risk for gastrointestinal bleeding with NSAIDs. Diabetics face an increased risk of renal complications. Because NSAIDs are associated with adverse renal effects, they should be used cautiously in patients with advanced renal disease. Acetaminophen is the most appropriate initial analgesic for African Americans with chronic osteoarthritic pain and concurrent hypertension, CVD risk factors or diabetes, and is recommended by the American College of Rheumatology as first-line treatment. Many of the adverse effects commonly associated with NSAIDs are not associated with acetaminophen. Safety concerns surrounding pharmacologic treatment of osteoarthritis in African Americans are reviewed.