Osteoarthritis is a chronic condition involving degeneration of cartilage within the joints. It is the most common form of arthritis and is associated with pain, substantial disability, and reduced quality of life. About 6 percent of U.S. adults aged 30 years or older have symptomatic osteoarthritis of the knee, and 3 percent have symptomatic osteoarthritis of the hip. Osteoarthritis increases with age: the incidence and prevalence increase two- to tenfold from age 30 to 65 and continue to increase after age 65. The total costs for arthritis, including osteoarthritis, may be greater than 2 percent of the gross domestic product, with more than half of these costs related to work loss. Common oral medications for osteoarthritis include non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. Patients with osteoarthritis also use over-the-counter supplements not regulated by the U.S. Food and Drug Administration (FDA) as pharmaceuticals, including glucosamine and chondroitin, as well as topical agents. Opioid medications are also used for selected patients with refractory, chronic pain but are not recommended for first-line treatment of osteoarthritis and therefore not included in this review. Each class of medication or supplement is associated with a unique balance of risks and benefits. In addition, efficacy and safety may vary for individual drugs within a class. Nonpharmacologic interventions (such as physical therapy, weight reduction, and exercise) also help improve pain and functional status in patients with osteoarthritis. A challenge in treating osteoarthritis is deciding which medications will provide the greatest symptom relief with the fewest serious adverse effects. NSAIDs decrease pain, inflammation, and fever by blocking cyclooxygenase (COX) enzymes. Understanding of the pharmacology of NSAIDs continues to evolve, but it is now thought that most NSAIDs block three different COX isoenzymes, known as COX-I, COX-2, and COX-3. COX-I protects the lining of the stomach from acid. COX-2 is found in joint and muscle, and mediates effects on pain and inflammation. By blocking COX-2, NSAIDs reduce pain compared to placebo in patients with arthritis, low back pain, minor injuries, and soft tissue rheumatism. However, NSAIDs that also block the COX-I enzyme (also called "nonselective NSAIDs") can cause gastrointestinal bleeding. In the United States, there are an estimated 16,500 annual deaths due to NSAID-induced gastrointestinal complications, a higher death rate than that for cervical cancer or malignant melanoma. Theoretically, NSAIDs that block only the COX-2 enzyme (also called "coxibs," "COX-2 selective NSAIDs," or "selective NSAIDs") should be safer with regard to gastrointestinal bleeding, but they also appear to be associated with increased rates of serious cardiovascular and other adverse effects. Less is known about COX-3, which is found in the cerebral cortex and cardiac tissue and appears to be involved in centrally mediated pain. For this report, we defined the terms "selective NSAIDs" or "COX-2 selective NSAIDs" as drugs in the "coxib" class (celecoxib, rofecoxib, valdecoxib, etoricoxib, lumiracoxib). We defined "partially selective NSAIDs" as other drugs shown to have partial in vitro COX-2 selectivity (etodolac, nabumetone, meloxicam). Aspirin differs from other NSAIDs because it irreversibly inhibits platelet aggregation, and the salicylic acid derivatives (aspirin and salsalate) were considered a separate subgroup.