The definitive diagnostic criteria for malignant adrenocortical tumors are distant metastasis and/or local invasion. The Weiss histopathologic system is the most commonly used method for assessing malignancy because of its simplicity and reliability. Unfortunately, its application remains subjective. This current retrospective study evaluated the Weiss system and assessed the value of MIB-1 labeling in the diagnosis of adrenocortical malignancy. Twenty-four malignant tumors with distant metastasis, gross local invasion, or recurrence were selected and matched on their functioning status to 25 benign tumors. Two independent observers delineated the Weiss criteria. An MIB-1 labeling index was determined. Presence of three or more Weiss microscopic criteria was related to malignancy (specificity 96%, sensitivity 100%), thus confirming the value of the Weiss system. Interobserver agreement for the Weiss system (total score) was excellent (r = 0.94). The lack of reliability for some Weiss criteria led us to propose a statistically modified system, based on the most reliable criteria (2.mitotic rate x 2.cytoplasm x abnormal mitoses x necrosis x capsular invasion) with a significant correlation with the Weiss system (r = 0.98). The MIB-1 labeling index was significantly higher in malignant tumors (p <0.0001). MIB1 could also help to differentiate malignant from benign adrenocortical tumors.