BACKGROUND: Challenges in the diagnosis of polypoid gallbladder lesion (PLG) is due to the low sensibility (SE) of ultrasound scan (US), and the selection criteria of patients with PLG to be addressed to surgical treatment or followup are not yet fully defined. MATERIALS AND METHODS: Retrospective observational study was conducted on 2631 patients, 1175(44.6%) M, mean age 56 years, 1456(55.4%) F, mean age 46 years, who underwent laparoscopic and open cholecystectomy. RESULTS: The US diagnosis for PLG was placed in 38/2631(1.4%) patients. On histological examination (HE) the polyps were identified in 68/2631(2.6%) patients and it was associated with biliary lithiasis in 28/2631 (1.1%) cases. From the US and HE comparison, the ultrasound diagnosis was burdened by false positives (8/38; 21%) and false negatives (38/2631;1.45%), with SE 44% (95% c.i.:32.2-55.7). The histological incidence of gall bladder cancer (GBC) was 0.38%(10/2631). DISCUSSION: US survey underestimated the incidence of PLG compared to the histological finding (p=0.021). Female gender has been shown to be a specific risk factor for benign and malignant PLG and non-polypoid mucosal lesions (p=0.041). The parietal lesion size <0.5cm does not exclude the neoplastic nature. Currently the prevention and diagnosis of GBC is based on the early detection and treatment of potentially evolutionary polypoid lesions over a period of about 15 years. CONCLUSIONS: It is probably that early cholecystectomy in all the patients with PLG of diameter <1cm, isolated or associated with lithiasis, symptomatic and asymptomatic, can contribute to the reduction of the incidence of GBC.