Background: Different etiologies of chronic liver disease (CLD) potentially lead to hepatocellular carcinoma (HCC) by multiple mechanisms that can be translated into clinicopathological and prognostic differences. We evaluated the expression of some proteins of MAPK pathway, an important signalling cascade in HCC, and correlated them to clinical and histopathological parameters, and long-term outcome, according to the etiology of the CLD. Methods: 80 patients (pts) who underwent orthotoptic liver transplantation (OLT) for HCC at Universidade Federal de Minas Gerais, a referral center in Brazil, were randomly selected: 41 viral (V) (HBV or HCV infection), 39 nonviral (NV) (alcohol abuse and cryptogenic) etiology. Clinical pre-OLT and histological data were retrospectively collected. Event (E) was defined as death and/or HCC-recurrence since OLT. In explanted liver, tumor and adjacent cirrhosis were subjected to immunohistochemistry, using antibodies against K-RAS, B-RAF and MEK, analysed by two pathologists. Results: V and NV groups were well balanced regarding clinicopathologic indices, but alcohol was the main etiology in men (95%) and HCV in women (38.7%). Median E-free survival (EFS) was 74.5 months (range, 8.5-105), without difference between groups. Microvascular invasion (MIV) (p < 0.01) and age (p = 0.04) were independently associated with E. 11 pts (26.8%) of the V group had strong expression (SE) of K-RAS in tumor comparing to 0 (0%) in cirrhosis (p = 0.008) and to three (7.7%) in NV group HCC (p = 0.024). SE of B-RAF was seen in seven pts (17.0%) in V versus 11 (28.2%) in NV (p = 0.257), without difference from cirrhosis (p = 0.755). SE of MEK was not seen. Weak KRAS expression was more common in older pts (p = 0.04). The proteins expression was not related to E or EFS. Conclusions: SE of K-RAS, but not of BRAF and MEK, were more frequent in V group HCC than in cirrhosis and NV group tumors. It suggests that HBV and HCV can lead to HCC by different mechanisms comparing to NV etiology and KRAS could have a role on carcinogenesis. As there were no differences in clinical outcomes, prognostic, and therapeutic implications need to be stablished.