Pocket-size ultrasound devices (PSUD) are now widely available becoming a useful tool for diagnostic and therapeutic purposes. We aim to investigate the accuracy of PSUD in diagnosing cholelithiasis as compared to traditional ultrasonography. Moreover, we tested the reliability of PSUD when performed by inexperienced internal medicine residents after a short-term training. We consecutively enrolled inpatients and outpatients referred to undergo abdominal ultrasonography for signs or symptoms of gallbladder diseases in two different hospitals. Every patient underwent two independent examinations with PSUD by both expert (EXPPSUD) and nonexpert operators (N-EXPPSUD), and a conventional examination with traditional abdominal ultrasound (AUS). Every naive operator underwent a short-term training with a 2-h theoretical lesson, and a practical training focused on gallbladder under expert operator supervision. Overall, 146 patients were consecutively enrolled. Considering conventional AUS as the reference standard, sensitivity and specificity of EXPPSUD were, respectively, 93.75 and 100%. Sensitivity and specificity of N-EXPPSUD were, respectively, 75 and 91.25%. Nevertheless, when considering outpatients, PSUD has a high diagnostic accuracy even when performed by N-EXPPSUD with sensitivity of 93% and specificity of 88%. PSUD is a reliable tool for the diagnosis of cholelithiasis when used by expert operators potentially reducing the need for further diagnostic tests. It can even be successfully used by non-expert operators in outpatients setting after a short focussed training.