Nipple discharge (ND) is a common symptom seen in breast cancer clinics. The primary aim of this study was to identify preoperative risk factors for breast cancer in patients with pathologic ND. The secondary aim was to assess the clinical and pathological effectiveness of physical examination, galactography, cytological examination of the discharge, selective duct excision and ductoscopy. All patients operated on between 1975 and 2008 who presented with ND as their only symptom was analyzed. Discharge’s characteristics, cytological data and galactography reports were recorded. The relationship between each individual finding and the risk of breast cancer was calculated. For each diagnostic tool, the sensitivity, specificity and complication rates were calculated and compared. Nine-hundred-fifteen patients underwent selective duct excision. Two-hundred-nineteen patients (23.9%) were found to be affected by carcinoma. In 100/330 (30.3%) patients with bloody discharge and in 42/239 (17.6%) patients with serous secretion cancer was detected (P = 0.004, P = 0.013, respectively). Patients with sero-sanguinous or coloured discharge had the same risk of cancer as the population analyzed (23.9%, P = NS). Galactographic finding of irregular stenosis seemed to be associated with a higher risk of cancer (P = 0.0001). Cytological findings C5 and C4 were associated with cancer (P = 0.001). Selective duct excision showed highest sensitivity and specificity. In conclusion, the well established role of bloody secretion is confirmed. The supposed benign aetiology of serous, coloured or sero-sanguinous discharge is questionable. The high specificity of the cytological exam justifies routine examination of the ND. Selective duct excision can be considered as the diagnostic gold-standard.