Background Endoscopic mucosal resection (EMR) is today the treatment of choice for flat and sessile colorectal lesion, the only concern being completeness of resection. One of the major issues is the choice of the infiltrating substance to enable a long-lasting cushion under the lesion. The aim of this study was to prospectively evaluate safety and efficacy of hydroxy-propyl-methyl-cellulose (HPMC) injection for this purpose. Patients All flat and sessile lesions of the colon and rectum larger than 20 mm and considered suitable for EMR were included. In all cases 0.8% HPMC solution was injected through a 23G needle, in quantity according to the endoscopist’s indication. Primary endpoints of the study were: (1) ability to perform en bloc resection of the lesions by using this new injection means, (2) complete resection rate, and (3) early and late complication rate. Results We resected 27 flat, sessile, or laterally spreading lesions up to 60 mm (28 mm average). Mean dose of HPMC injected was 10.2 ml (range 8–40 ml). Median procedure time was 32 min (range 15–105 min). En bloc resection was achieved in up to 21 cases (78%). Histologically detected complete tumour removal was achieved in 23 lesions, whereas lateral margins could not be properly evaluated in 4 cases due to coagulation artefacts. No perforation was observed. Procedural spurting bleeding was managed by epinephrine injection in one case and clip application in the remaining. Two case of local recurrence of adenomatous tissue were observed at 3 and 12 months, and treated byEMR. No complication related to the use of HPMC was observed. Conclusions Injection of HPMC for EMR resulted safe and effective, allowing en bloc resection in the majority of cases with a limited number of complications. Continued progress in the field will include more outcomes research and techniques simplification.