Endocrine tumors of the pancreas are slow-growing lesions, yet one-third to one-half will metastasize. It is generally accepted that histopathologic features do not reliably predict metastatic potential or outcome. We investigated whether proliferative activity, as determined by MIB-l labeling, correlated with tumor type, metastasis, or patient survival. Formalin-fixed sections of pancreatic endocrine tumors were immunohistochemically stained for the MIB-l antibody against Ki-67 using the avidin-biotin complex technique. Labeling index (LI) was determined by counting 1000 consecutive tumor cells in an area of greatest staining intensity at x400 and expressed as a percentage. The study group included 37 patients, including 10 gastrinomas, 9 insulinomas, 4 glucagonomas, 2 VlPomas, and 12 nonfunctioning tumors. Twenty-one patients had metastases, primarily to regional lymph nodes and the liver. Five patients had MEN I. MIB-1 LI was significantly greater in the nonfunctioning tumors (mean 20S%) than in the functioning tumors (mean 51%) (p = 0.01). LI for functional tumors (insulinomas 64%, glucagonoma 44%, gastrinomas 32%, VlPomas 32%) were similar to each other, MIB-1 was significantly higher in those tumors that metastasized (mean 15.6%) compared to those that did not (mean 31%), (p = 0.04). All tumors with MIB-1 LI >10% developed metastases. Logistic regression showed that MIB-1 was a significant predictor of metastases (p = 0.003) after adjusting for functional status. MIB-1 LI also correlated with outcome in that those patients with MIB-1 LI >/=10% had a mean survival of 19 mo compared to 72 mo for those with levels <10% (p = 0.0001). Results of the proportional hazards model showed that MIR-1 remained a significant (p = 0.03) and independent predictor of survival times after adjustment for tumor size and functional status. Higher MIB-1 LI values were significantly associated with shorter survival times. In conclusion, MIB-1 LI appears to be a useful indicator of metastatic potential and is predictive of outcome in PET.