Background: Identification of HCC pts with higher probability of benefit from sorafenib warrants investigation. Hypertension (HTN) and hand foot syndrome (HFS) are sorafenib-specific toxicities; the development of these toxicities is prognostic in pts with renal cell cancer receiving sorafenib, their significance in HCC remains uncertain. Methods: HCC pts treated with sorafenib at the Christie NHS Foundation Trust (Nov-09-Feb-15) were identified. The primary end-point was overall survival (OS). Kaplan-Meier and Cox regression models were employed for identification of prognostic factors. Results: Eighty-five eligible pts were identified [median follow-up 6.2 months (range: 0.4-31.4)].Median age 68 yrs (range 29-89); 87% male; 80% background liver cirrhosis ;88% ECOG performance score 0/1; Child-Pugh (CP) A5 (64%), A6 (29%) and B (7%); 41% baseline AFP > 400 IU/L; 45% previous liver-directed therapy. Sorafenib (400mg BD),was started in 68% (median dose intensity 49.9% (range 0.7-100)), remaining patients started at reduced dose. Fifty-one percent had pre-existing HTN (91% treated).The most common grade ≥ 3 treatment-related toxicities were HTN (42% no prior history of HTN), fatigue (8%), and HFS (8%);59% of pts developed any grade HFS and/or worsening HTN (HFS/HTN). Toxicity-related dose reduction/cessation was required in 46 (54%) pts (15% due to HFS, 7% due to HTN). Estimated median progression-free (PFS) and OS were 5.5 (95% CI 4.1-7.0) and 6.5 (95% CI 4.9-8.0) months, respectively. Age at diagnosis, previous liver-directed therapy, CP score, baseline AFP and development of HFS/HTN were included in multivariable analysis: CP-A (vs. B; p-value < 0.001) and development of HFS/HTN (vs. no; HR 0.4 [95% CI 0.2-0.7] p-value 0.001) were independent prognostic factors. The prognostic influence of HFS/HTN was preserved when limiting analysis to pts developing worst grade HFS/HTN in the first 3 months of treatment (53 pts; HR 0.5 [95% CI 0.3-0.9] p-value 0.030) making time-on-treatment bias unlikely. Conclusions: The development of sorafenib-specific toxicities, HFS and HTN, are prognostic factors associated with prolonged OS.