Purpose: PR-104 is activated by reductases under hypoxia or by aldo-keto reductase 1C3 (AKR1C3) to form cytotoxic nitrogen mustards. Hepatocellular carcinoma (HCC) displays extensive hypoxia and expresses AKR1C3. This study evaluated the safety and efficacy of PR-104 plus sorafenib in HCC. Methods: Patients with advanced-stage HCC, Child-Pugh A cirrhosis, and adequate organ function, were assigned to dose escalating cohorts of monthly PR-104 in combination with twice daily sorafenib. The plasma pharmacokinetics (PK) of PR-104 and its metabolites were evaluated. Results: Fourteen (11 men, 3 women) HCC patients: median age 60 years, ECOG 0-1, received PR-104 at two dose levels plus sorafenib. Six patients were treated at starting cohort of 770 mg/m 2. In view of one DLT of febrile neutropenia and prolonged thrombocytopenia, a lower PR-104 dose cohort (550 mg/m2) was added and accrued 8 patients. One patient had a partial response and three had stable disease of =8 weeks in the 770 mg/m2 cohort. Three patients at the 550 mg/m2 had stable disease. There were no differences in PK of PR-104 or its metabolites with or without sorafenib, but the PR-104A AUC was twofold higher (P <0.003) than in previous phase I studies at equivalent dose. Conclusions: PR-104 plus sorafenib was poorly tolerated in patients with advanced HCC, possibly because of compromised clearance of PR-104A in this patient population. Thrombocytopenia mainly and neutropenia were the most clinically significant toxicities and led to discontinuation of the study. PR-104 plus sorafenib is unlikely to be suitable for development in this setting.