Purpose Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (>99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients. Results In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 μM CI95 0.20–0.23. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 μM) to 30 g/L (453 μM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75–2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL ( p  = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia ( p  = 0.0036) was the single parameter independently associated with CL. Conclusion These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients.