BACKGROUND Tumors of the lacrimal drainage system are rare but potentially life-threatening. The purpose of this study was to investigate the applicability of selective lacrimal sac biopsy in 500 cases of external dacryocystorhinostomy for acquired dacryostenosis. METHODS Lacrimal sac biopsy was obtained selectively for atypical clinical and/or intraoperative findings. The frequency and spectrum of biopsies were recorded and correlated with the follow-up results. RESULTS Lacrimal sac biopsy was performed in 19 external dacryocystorhinostomies (3.8%) including non-Hodgkin B-cell lymphoma (3), squamous carcinoma (2), mucoepidermoid carcinoma (1), malignant melanoma (1), oncocytoma (1), pyogenic granuloma (4), Wegener's granulomatosis (4) and sarcoidosis (3). Within 5 years none of the patients without biopsy developed systemic inflammatory diseases or lacrimal neoplasms. The 5-year survival was 87% in patients with significant lacrimal sac pathology and 96% in patients without significant pathology. CONCLUSIONS External dacryocystorhinostomy with selective biopsy for atypical clinical and intraoperative findings allows safe diagnosis and management of potentially life-threatening lacrimal lesions.