There is no consensus about the diagnostic approach to pathologic nipple discharge (PND). We hypothesize that lactiferous duct excision (microdochectomy) or image-guided biopsy are safe and effective means of diagnosis of PND. Eighty-two patients with PND underwent history and physical exam followed by breast sonography and mammogram. Image-guided biopsy was done if imaging studies were positive, whereas microdochectomy was done if normal. Discharge was unilateral (96%), bloody (79%), and spontaneous (62%). The sensitivity, specificity, positive and negative predictive values for the detection of neoplasia were 0.07, 1.0, 1.0, and 0.4 for mammography and 0.26, 0.97, 0.91, and 0.48 for sonography, respectively. Tissue diagnosis revealed papillary lesion (57%), mammary duct ectasia (33%), breast cancer (5%), and inflammatory/infectious (5%) causes. Hemorrhagic discharge associated with pregnancy or infections was managed successfully without surgery. After a median follow-up of 18 months, no PND recurrence was seen, but one patient developed cancer in a different location after diagnosis of atypical ductal hyperplasia. In conclusion, imaging studies provide confirmatory information and a biopsy target when positive. Negative imaging does not reliably exclude neoplasia or malignancy. Microdochectomy provides a sensible and effective approach in the workup of patients with PND.