We report a 63-year-old woman who developed theophylline toxicity on two separate occasions after the addition of ranitidine to her drug regimen. The first incident occurred during hospitalization, when the patient developed classical signs of theophylline toxicity (e.g., nausea, anxiousness, tremor, cardiac arrhythmias) within 48 hours after the addition of ranitidine to her drug regimen. Her theophylline concentration on the third day of overlap of these medications was 312.4 mumol/L while she was receiving sustained-release theophylline 300 mg q4h. A concentration obtained 14 days prior to admission was 115.5 mumol/L when she was receiving a comparable dosage of theophylline (300 mg five to six times a day, depending on the need for a nighttime dose). The second incident involved the unintentional rechallenge of the patient with oral ranitidine, on an outpatient basis, which again resulted in clinical theophylline toxicity with a rise in concentrations from 104.5 to 187.6 mumol/L. In both instances, the theophylline concentrations returned to expected values for this patient with the discontinuation of ranitidine. The rechallenge of this patient with ranitidine substantiated our initial suspicion that a ranitidine-theophylline drug interaction occurred in this patient. The possibility of such an interaction was further supported by other case reports in the literature. These case reports are contrary to controlled studies which show no evidence of a ranitidine-theophylline drug interaction. However, the number of subjects in such studies are small, and our case report and others suggest that this drug interaction may occur in select patients.(ABSTRACT TRUNCATED AT 250 WORDS)