This study aimed (1) to develop a simple scoring system incorporating ultrasound (US) examination and clinical or laboratory predictors for increasing diagnostic accuracy in acute appendicitis (AA), and (2) to evaluate the performance of the scoring system as compared to that of previous models. Fifteen variables including US assessment for patients admitted with suspected AA were considered in multivariate analysis using the finding of AA at operation as the end point (internal study). The new score, together with 11 previous ones, was applied to a prospective independent population of subjects with suspected AA, and the respective performances were compared (external validation study). Among 303 patients (170 males, mean age 28.3 ± 13.3 years) of the internal study, 161 went on to surgery, and 130 had AA at operation. Four independent correlates of AA were identified and used for the derivation of the following integer-based scoring system: number of points = 6 for US demonstrating AA + 4 for tenderness in the right lower quadrant + 3 for rebound tenderness + 2 for leukocyte count >12,000/μl. In the external study (201 subjects, 105 males, mean age 28.7 ± 11.9 years, 109 operated, 87 with AA), when the cut-off of ≥ 8 points for AA was used, sensitivity, specificity, accuracy, and area under the curve of the proposed score were 95.4%, 97.4%, 96.5%, and 93%, respectively, exceeding noticeably the previous models. The proposed scoring system introduces a quantitative combination of the clinical evaluation with US imaging and a marker of inflammatory response, which may enhance the diagnostic accuracy for subjects with suspected AA especially in geographical areas where CT scanning is not readily available on a 24-hour basis.