Raltegravir (RAL) is primarily metabolized by uridine diphosphate-glucorunosyl transferase 1A1 (UGT1A1). Atazanavir (ATV), a strong inhibitor of UGT1A1, has been shown to increase plasma concentrations of RAL by approximately 50% in healthy volunteers. However, the extent of this interaction has not been studied in HIV-infected patients. A pharmacokinetic study was performed in 22 HIV-infected adults treated with 400 mg RAL plus 300 mg ATV 300 twice a day. Both drugs showed high pharmacokinetic variability (RAL AUC 0-12 7649 ± 4862 ng*h/mL; ATV AUC 0-12 = 19237 ± 13136 ng*h/mL). Notably, RAL trough concentrations were significantly higher compared with those measured in HIV subjects (n = 24) on RAL plus nucleoside reverse transcriptase inhibitors (506 ± 411 versus 177 ± 262 ng/mL, P < 0.01). A significant correlation was found between RAL and ATV area under the curve (AUC) (r = 0.611, P = 0.005). Notably, patients with ATV AUC 0-12 above the mean or with concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had twofold higher RAL AUCs compared with patients with lower ATV exposure. Coadministration of ATV significantly increased plasma concentrations of RAL, especially in HIV-1-infected patients exposed to high concentrations of the protease inhibitor. This pharmacokinetic drug interaction could be handled by routine measurements of ATV trough concentrations and by the assessment of plasma RAL concentrations 2 to 3 hours after the morning drug intake.