Background EMR traditionally is performed by using normal saline solution (NS) as the submucosal fluid cushion. It is thought, however, that NS does not maintain the proper mucosal elevation for EMR of large, flat lesions. We investigated the efficacy of glycerol as the submucosal injection solution. Methods A total of 110 colorectal laterally spreading tumors (LST) were treated by EMR with glycerol. For comparison, 113 LSTs treated by using NS were studied. The en bloc resection, complete resection, and associated complications rates were evaluated retrospectively. Observations The en bloc resection rate in the glycerol group was 63.6% (70/110) compared with 48.9% (55/113) in the NS group (p < 0.05). The complete resection rate in the glycerol group was 45.5% (50/110) compared with 24.6% (28/113) in the NS group (p < 0.01). The associated complications rate was similar in both groups. Conclusions It technically was easier and as safe to perform EMR of colorectal LSTs when using glycerol as the submucosal injection solution.