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Objectives The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (Ctot) predicts cellular concentration (Ccell). Methods Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. Ctot and Ccell of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the Ccell/Ctot ratio. Results Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (Cmax), minimum concentration (Cmin) and area under the time–concentration curve from 0–12 h (AUC0–12) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular Cmax, Cmin and AUC0–12 were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir Ccell corresponded to 5.3% of Ctot measured simultaneously. Both concentrations fluctuate in parallel, with Ccell/Ctot ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUCcell/AUCtot GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively. Conclusions Raltegravir Ccell correlated with Ctot (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated. [ABSTRACT FROM PUBLISHER]