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As such, the natural history of MPD-involved IPMN is poorly understood.The high-risk of malignancy associated with main pancreatic duct (MPD)-involved intraductal papillary mucinous neoplasm (IPMN) has been established by surgical series. The International Consensus Guidelines recommend surgical resection of MPD-involved IPMN in fit patients.A review of a prospectively collected database (1992–2012) of patients with IPMN undergoing primary surveillance was performed. Invasive progression was defined as invasive carcinoma on pathology and/or positive cytopathology. Analyses included univariate, logistic regression, and receiver operating characteristic curve analyses.A total of 503 patients with IPMN underwent primary surveillance, 70 for MPD-involved, mixed-type IPMN. Indications for intensive surveillance of these 70 high-risk patients were comorbidities, patient choice, and early/borderline MPD dilation (42%, 51%, and 7%, respectively). Mean follow-up was 4.7 years. Nine patients (13%) progressed at a mean of 3.5 (range, 1–9) years during follow-up. Univariate analyses yielded weight loss, interval (from isolated branch-duct IPMN) to MPD involvement, diffuse MPD dilation, increase of MPD diameter, absence of extra pancreatic cysts, elevated serum CA19-9 levels, and elevated serum alkaline phosphatase levels as significant. Maximum MPD and/or branch-duct diameter were not significant. In logistic regression, diffuse MPD dilation, serum CA19-9 and serum alkaline phosphatase levels, and absence of extra pancreatic cysts were predictors of invasiveness. The receiver operating characteristic curve indicated that the combination of these 4 factors achieved an accuracy of 98% in predicting progression.Primary surveillance of mixed-type IPMN may be a reasonable strategy in select patients. Diffuse MPD dilation, serum CA19-9, serum alkaline phosphatase, and absence of extrapancreatic cysts predict patients likely to progress during primary surveillance.