Terfenadine is a nonsedating histamine H1-antagonist that, when given with ketoconazole, results in accumulation of parent terfenadine and altered cardiac repolarisation in susceptible individuals. This prospective cohort study, designed to assess macrolide effects on terfenadine pharmacokinetics and electrocardiogram (ECG) parameters, evaluated 18 healthy male and female volunteers who received terfenadine to steady-state. Equal numbers (6) were randomised to receive either erythromycin, clarithromycin or azithromycin at recommended doses while continuing terfenadine. Macrolide monotherapy effects on the ECG were also investigated. Pharmacokinetic profiles for terfenadine were performed before and after the addition of macrolide therapy, and ECGs were obtained at baseline and predose on days of blood sampling.Erythromycin and clarithromycin significantly affected the pharmacokinetics of terfenadine. Three of 6 volunteers receiving erythromycin and 4 of 6 receiving clarithromycin demonstrated accumulation of quantifiable unmetabolised terfenadine that was associated with altered cardiac repolarisation. Azithromycin had no effect on terfenadine pharmacokinetics or cardiac pharmacodynamics.