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Secondary acquired nasolacrimal duct obstruction (SANDO), where the obstruction is caused by a known process, is becoming more commonly treated by endoscopic dacryocystorhinostomy (endoDCR). This study evaluates outcomes of endoDCR for cases of SANDO in comparison to endoDCR outcomes treating primary acquired nasolacrimal duct obstruction (PANDO).All patients undergoing endoDCR from 2006 to 2015 at a tertiary referral center were reviewed for etiology of nasolacrimal duct obstruction (NLDO) and success of procedure. Inclusion criteria were preoperative determination of NLDO via probing and irrigation, greater than 60-day follow up with assessment of duct patency via probing and irrigation after silicone tube removal, and postoperative survey for recurrent epiphora. Exclusion criteria were cases treating partial NLDO, patients undergoing concurrent conjunctivodacryocystorhinostomy, and patients lost to follow up or with incomplete records. Preanalysis stratification was performed for the following preexisting conditions: PANDO, granulomatosis with polyangiitis, sarcoidosis, midfacial radiotherapy, radioactive iodine therapy, severe prolonged sinusitis, prior failed DCR, and midface trauma. The primary outcome was postoperative anatomical patency of the nasolacrimal system with resolution of epiphora. Fisher–Freeman–Halton exact tests were performed comparing each SANDO group to the PANDO group with statistical significance set at p < 0.05.Fifty-nine cases of NLDO underwent endoDCR in this series, 21 of which had a diagnosis consistent with SANDO. All patients treated with the aggressive perioperative management protocol the authors describe achieved anatomical patency. Patients with history of radioactive iodine therapy and radiotherapy had statistically worse outcomes compared with patients with PANDO, p = 0.011, p = 0.045, respectively. Stratified groups with increased intranasal sinus inflammation trended toward worse outcomes, but were not statistically different.EndoDCR is a viable approach for the treatment of SANDO. In patients with history of radiotherapy or radioactive iodine therapy, however, endoDCR demonstrated decreased success rates as compared with patients with PANDO. Modifications of operative and postoperative management based on underlying etiology of NLDO may improve outcomes of endoDCR in SANDO cases. The authors describe an aggressive protocol for perioperative management of patients with pathologic nasal inflammation undergoing endoDCR.