The pharmacokinetic drug interactions between lithium sulfate and the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and aspirin were studied in ten normal female volunteers restricted to 150-mEq/day of sodium. Indomethacin decreased renal lithium ion elimination by 23% and caused a 40% increase in steady state plasma lithium ion levels. In contrast, aspirin had no effect on plasma lithium ion levels and increased renal lithium ion elimination by only 6%. Renal prostaglandin E2 excretion was suppressed by 50% to 60% of control levels by indomethacin and by 65% to 70% by aspirin. A clinically important drug interaction with the risk of lithium intoxication can occur between lithium salts and indomethacin. However, aspirin did not affect steady state plasma levels of lithium ion and thus may be preferable for antirheumatic treatment of patients undergoing long-term therapy with lithium salts. Frequent monitoring of plasma lithium ion levels is absolutely necessary in patients receiving both lithium salts and NSAIDs.