Routine regional lymphadenectomy for colorectal liver metastases and primary liver tumors is still a subject for debate. During 2001-2005, we performed a prospective study of cases in which regional lymphadenectomy around the hepato-duodenal ligament and common hepatic artery was applied (group R+ LN) or not (group R- LN). Pre-operative clinical features of patients were comparable among groups as well as the operative data. There were 108 (67%) males; the median age was 66 years; 124 cases had a single lesion (77%), and the median diameter was 4 cm. The type of lesion was: 77 (48%) colorectal liver metastases (M-CR), 75 (46%) hepatocellular carcinomas (HCC) and 10 (6%) cholangiocellular carcinomas. In the R+ LN group, the mean number of lymph nodes removed was 6.7 ± 4.8 (range 4-26), and seven cases (8.6%) presented lymph node metastasis. The median follow-up was 3.5 years. M-CR patients showed comparable hospital mortality (R+ LN 0% vs. R- LN 2.6%) and morbidity (R+ LN 17.9% vs. R- LN 21.1%), but R+ LN had higher 5-year disease-free survival (31 vs. 16%, p < 0.05). HCC cases in the R+ LN group presented higher hospital mortality (13.5 vs. 0%, p < 0.05) without any improvement in disease-free survival (it was at 5-year disease-free survival 34 vs. 33%, respectively, p = n.s.). Routine regional lymphadenectomy should be performed for colorectal liver metastases, and avoided in patients with hepatocellular carcinoma.