Conventional grayscale ultrasound (US) is accurate in the diagnosis of gallbladder disease (GD), but in some cases, it is not decisive. Contrast-enhanced ultrasound (CEUS) improves the diagnostic accuracy of US. The primary objective of this study is to assess the reliability of CEUS in the diagnosis of sludge; the secondary objective is to assess the ability of CEUS to diagnose cancer. We retrospectively reviewed the US of 4137 patients positive for GD. In 43/4137 (1.04%), the use of could not discriminate between sludge and neoplasms. Then, we evaluated CEUS in only 39 of these patients, and in 4/43 (9%) cases it was not performable. After CEUS, the absence of enhancement was considered diagnostic for sludge, while contrast washout within 60s diagnosed malignant lesions. Among the 39 patients, 16 had biliary sludge and 23 had lesions of the gallbladder wall; 9 of these were carcinomas and 14 were benign tumors. The absence of enhancement was present in 16/16 patients with sludge and in 0/23 patients with lesions of the gallbladder (sensitivity and specificity 100%). Washout was within 60s in 9/9 gallbladder carcinomas and 2/14 benign lesions (sensitivity 100%; specificity 85%). US is confirmed to be accurate in the diagnosis of GD. In doubtful cases, CEUS is very accurate in biliary sludge diagnosis. An intralesional washout at 60s is a pattern of malignancy that can orient towards a correct diagnosis, but it is limited by the presence of false positive results, especially for smaller lesions.