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Introduction: Locally advanced penile cancer is rare, with few reported studies on the therapeutic role of chemoradiotherapy. We sought to characterize the efficacy and toxicity of definitive chemoradiotherapy for locally advanced, node-positive, squamous cell carcinoma of the penis., Materials and Methods: Six patients who had refused or were ineligible for surgical resection of clinically staged node-positive squamous cell penile cancer were treated with definitive chemoradiotherapy using either weekly cisplatin or 2 cycles of mitomycin C/5-fluorouracil. The mean radiation dose to the primary sites, involved lymph nodes, involved nodal basins, and uninvolved nodal basins was 57.2, 55.0, 49.7, and 42.3 equivalent dose delivered in 2-Gy fractions., Results: With a median follow-up of 7.2 years, 4 of the 6 patients were recurrence-free and 2 had developed recurrence. One of the latter died of penile-specific complications after salvage surgery to treat the recurrence. Of the 6 patients, 4 experienced long-term penectomy-free survival. No patient developed distant metastasis after therapy. The 4 patients with durable penectomy-free survival reported excellent urologic, sexual, and bowel function, as assessed by various validated patient-reported outcome surveys and subjective reports. One of the 2 patients with recurrence was successfully salvaged with penectomy. Lymphedema and stricture were not reported by any of the patients., Conclusions: Definitive chemoradiotherapy is an effective organ-sparing treatment of node-positive penile cancer, with durable disease control and maintenance of quality of life. This treatment option should be offered to carefully counseled patients within the context of expert multidisciplinary teams and should be incorporated into expert consensus treatment guidelines., (Copyright © 2020 Elsevier Inc. All rights reserved.)