A case report described a 52-year-old man on a stable ART regimen of rilpivirine (25 mg once daily), tenofovir alafenamide (25 mg once daily) and emtricitabine (200 mg once daily) with consistent virological suppression in the past 15 months. Control rilpivirine trough levels were 89 ng/ml but dropped to <20 ng/ml one month after the patient started to take ursodeoxycholic acid (300 mg twice daily) for the treatment of symptomatic intrahepatic stones. The patient reported optimal compliance to antiretroviral treatment as also evidenced by the fact that emtricitabine and tenofovir concentrations were in the range of expected concentrations. Rilpivirine was replaced by darunavir/cobicistat. Subsequent TDM showed normal trough concentrations of darunavir (i.e., 2132 and 1851 ng/ml) in presence of ursodeoxycholic acid. In vitro studies have shown that ursodeoxycholic acid is a CYP3A4 inducer. Significant reduction of certain CYP3A4 substrates (i.e. nitrendipine or dapsone) has been reported in human studies. The authors concluded that the undetectable rilpivirine trough concentrations are likely explained by the inducing effect of ursodeoxycholic acid. Of interest, darunavir concentrations were not altered suggesting that the presence of cobicistat, a strong CYP3A4 inhibitor, could have compensated the inducing effect of ursodeoxycholic acid.