Drug interactions occur when the pharmacologic profile of one drug is altered by the administration of another drug. These interactions may be due to changes in absorption, distribution, metabolism or excretion. NSAIDs are associated with drug interactions but only a proportion are clinically relevant. Many are due to displacement of a drug from its plasma protein binding sites by NSAIDs which are tightly protein-bound. They may not occur with all NSAIDs but might be selective: most NSAIDs do not have clinically important interactions with oral hypoglycemic agents whereas phenylbutazone, azaprozone & aspirin prolong their half-life. Similarly phenylbutazone and azaprozone prolong coumadin's half-life. Lithium clearance may be decreased by indomethacin, piroxicam, phenylbutazone and diclofenac. Methotrexate (MTX) may be displaced from its binding protein sites by NSAIDs. This is generally not clinically relevant with low doses of MTX as utilized in rheumatoid arthritis patients with normal renal function. NSAIDs also may reduce renal blood flow, tubular excretion of drugs & renal prostaglandin production and may attenuate the effect of anti-hypertensive drugs. Renal failure & hyperkalemia have been reported in patients receiving triamterene & indomethacin. The clinician should be aware of important drug-drug interactions prior to prescribing NSAIDs. Continued scrutiny of these effects are indicated to increase the safety profile.