The risks of muscle adverse events related to use of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, increase significantly with the addition of interacting drugs to a patient's therapy. The mechanism for most statin drug interactions involves the cytochrome P-450 system, which provides an indication of which drugs may interact. However, it is difficult to predict the probability of a drug interaction in a given patient because there are individual differences in sensitivity to increased statin drug levels. Drug metabolism studies show simvastatin and lovastatin to be especially sensitive to the inhibiting effects of other drugs on the cytochrome P-450 3A4 (CYP3A4) isoenzyme. Atorvastatin metabolism is less affected by inhibitors of this isoenzyme. Case reports, postmarketing surveillance, and clinical trial data demonstrate the clinical effect of CYP3A4 inhibitors on statins. Also, through possible inhibition of statin biliary excretion and glucuronidation, gemfibrozil given concomitantly with rosuvastatin, lovastatin, and simvastatin significantly increases the risk of myopathy and rhabdomyolysis, a potentially life-threatening consequence of statin drug interactions.