Salicylates and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of painful disorders. This article reviews the efficacy, side effects, and costs of these agents and proposes a practical approach to using them in a cost-effective manner. Although there may be some differences in efficacy among available drugs, these do not appear sufficient to justify using the more expensive agents in most cases. Adverse effects, especially gastrointestinal (GI), add to the cost of using these drugs. Aspirin and all nonsalicylate NSAIDs share a risk of causing gastric ulcer, upper GI bleeding, and GI perforation. Prostaglandin inhibition by these agents may lead to reduced glomerular filtration rate and renal failure. There may be modest differences in GI and renal risks with the different agents, but these are minimal. Prophylaxis against gastric ulceration with anti-ulcer drugs has been recommended, and one agent, misoprostol, is approved for use in the United States for this purpose. Whether use of prophylaxis will increase or decrease the costs associated with NSAID therapy remains to be determined. Nonacetylated salicylates may cause less GI adverse effects and may be somewhat "renal sparing." Strategies that would reduce the cost of care for painful musculoskeletal disorders without compromising quality of care include using acetaminophen instead of an NSAID for noninflammatory disorders, trying nonacetylated salicylates as less expensive and safer alternatives to NSAIDs, using one agent at a time, allowing sufficient time to evaluate the therapeutic effect before changing agents, returning to the least expensive and/or safest drug if a trial of several in succession fails to find one that is clearly better, and reserving prophylactic use of antiulcer agents for patients who are at especially high risk and for whom anti-inflammatory effects are clearly needed.