Background Submucosal malignant masses (SMMs) and innocent bulges look similar on small-bowel capsule endoscopy (SBCE). In a previous observational study, 4 criteria associated with innocent bulges were recognized. Objective To devise and validate an index based on these criteria (smooth, protruding lesion index on capsule endoscopy [SPICE]) to discriminate SMMs from innocent bulges. Design Single-center, prospective study. Setting General hospital in Busto Arsizio, Italy. Patients This study involved 25 of 424 consecutive SBCEs performed on as many patients having SBCE findings of smooth, round, protruding lesions. Intervention Patients' evaluation up to the final diagnosis. At study entry, a short video clip of the lesion was obtained and deidentified for blind SPICE calculation. Main Outcome Measurements SPICE accuracy, using the final diagnosis of each patient as the criterion standard. Results Six patients had SMMs (4 GI stromal tumors, 2 neuroendocrine tumors), and 19 had innocent bulges. SPICE scores ranged from 0 to 4; they discriminated SMMs from innocent bulges ( P = .002). A SPICE value >2 had 83.3% sensitivity and 89.4% specificity, and the area under the curve was 0.90 (95% confidence interval, 0.72-0.98; P Limitations Single-center study; small sample size; no invasive ascertainment in 36% of patients. Conclusion SPICE is easy to calculate and useful for distinguishing SMMs from innocent bulges. An index >2 is predictive of SMM.