Anecdotal and uncontrolled studies have suggested that nonsteroidal anti-inflammatory drugs produce false-positive results in immunoassay urine tests for some drugs of abuse. This study was performed in 60 volunteers who took ibuprofen as either a single 400-mg dose, or 200 mg three times a day, or 400 mg three times a day, and in 42 patients taking ibuprofen, naproxyn, or fenoprofen in therapeutic regimens for more than 30 days. Of the 510 urines collected from 102 individuals during these dosage regimens, two gave false-positive tests for cannabinoid by enzyme-mediated immunoassay (EMIA), one after 1200 mg of ibuprofen in three divided doses for one day and one in a patient taking naproxyn on a chronic basis; none was falsely positive for benzodiazepines. Two urines were false-positive for barbiturates by fluorescence polarization immunoassay (FPIA), one in a patient taking ibuprofen and one in a patient taking naproxyn. These data, collected prospectively, demonstrate the small likelihood of a false-positive immunoassay test result for cannabinoids, benzodiazepines, or barbiturates after the acute or chronic ingestion of ibuprofen, or after the chronic ingestion of naproxyn or fenoprofen.