OBJECTIVE Two open-label, randomized, cross-over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate. METHODS Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co-administration of etravirine with tenofovir disoproxil fumarate on either days 1-8 or days 9-16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h. RESULTS The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration-time curve from 0 to 12 h (AUC(12 h)) for etravirine co-administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61-0.79) and 0.81 (0.75-0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC(24 h) was 1.16 (1.09-1.23) in Study 1 and 1.15 (1.09-1.21) in Study 2. CONCLUSIONS These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co-administered.