Primary acquired nasolacrimal duct obstruction (PANDO) of adults is a clinical syndrome of unknown cause, and the histopathology of the nasolacrimal duct has not been substantially studied. A technique of excisional biopsy of the soft tissue contents within the nasolacrimal canal during external dacryocystorhinostomy (DCR) is presented. No complications were associated with the biopsy technique in 14 cases. Two cases of lacrimal obstruction secondary to sarcoidosis and leukemia were discovered in biopsies of patients with the clinical syndrome of PANDO, demonstrating the value of routine biopsy during DCR. Biopsies revealed a spectrum of changes that correlated with duration of symptoms. Early cases revealed active chronic inflammation along the entire length of the narrowed nasolacrimal duct. Intermediate cases revealed focal resolution of the inflammatory process with fibrosis, while late cases showed fibrous obliteration of the entire duct. Although the first event in primary acquired nasolacrimal duct obstruction remains uncertain, clinicopathologic correlation suggests that compression of the duct by inflammatory infiltrates and edema precedes clinical chronic dacryocystitis.