Laterally spreading tumors (LSTs) are considered a special subtype of superficial colorectal tumor. This study was performed to characterize the clinicopathological features and examine activation of the Wnt/beta-catenin pathway in LSTs and protruded-type colorectal adenomas (PAs). Fifty LSTs and 54 PAs were collected, and their clinicopathological characteristics were compared. The expression of E-cadherin, beta-catenin, glycogen synthase kinase-3beta (GSK-3beta), phosphorylated GSK-3beta, (phospho-GSK-3beta), cyclin D1, and c-myc was investigated by immunohistochemical staining on serial sections. Patients with LSTs were significantly older than those bearing PAs (63.4 vs 47.4 years old; p<0.001). The mean size of LSTs was significantly larger than that of PAs (27.0 mm vs 14.6 mm; p<0.01). Forty-eight percent of LSTs were located in the proximal colon, which was significantly higher than that of PAs (18.5%; p<0.05). Expression of beta-catenin, phospho-GSK-3beta, cyclin D1, and c-myc was significantly increased in LSTs compared with PAs (p<0.05). However, E-cadherin and total GSK-3beta expression was not significantly different between the two groups. The level of beta-catenin expression correlated strongly with phospho-GSK-3beta, cyclin D1, and c-myc expression in LSTs but not in PAs. Our findings suggest that activation of the Wnt/beta-catenin pathway is more prevalent in LSTs than in PAs, suggesting that phosphorylation-dependent inactivation of GSK-3beta may be involved in LST carcinogenesis.