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Simple Summary: The primary treatment modality for anal cancer is chemoradiotherapy, but patients with locally advanced disease (i.e., large tumors and/or involvement of regional lymph nodes) have a high risk of treatment failure. The use of chemotherapy prior to radiotherapy (induction chemotherapy) can potentially shrink the tumor and/or eradicate small cancer cells with metastatic potential, with a chance of a better outcome. With this paper, the authors present 20 years of nationwide experience with intensified induction chemotherapy in the treatment of locally advanced anal cancer, which indicates a role for further investigation in the most advanced cases. Locally advanced squamous cell carcinoma of the anus (LASCCA) has a poor prognosis with a high risk of treatment failure calling for intensified therapy. We present the long-term follow-up of a nationwide cohort of LASCCA treated with intensified induction chemotherapy (ICT). The study included patients with LASCCA (T3-4N0 or T1-4N+) treated with at least one cycle of ICT (cisplatin, ifosfamide, leucoverin, and 5-flourouracil) between 1998–2018. Data were retrospectively collected from medical records, and statistics were performed in STATA 16.1. In total, 166 patients with LASCCA were identified. Following ICT, 157 patients (95%) received primary curative treatment with either radiotherapy (70%), chemoradiotherapy (27%), or abdominal perineal resection (3%). The overall local tumor response rate after ICT was 76% with 20 (13%) achieving complete local tumor response. After the primary treatment, 123 patients (79%) obtained complete response, and 27 underwent salvage surgery due to persistent disease. The median follow-up time was 6 years, local and distant failure rates 22% and 13%, respectively. The 3- and 5-year disease-free survival rates were 70% and 67%, and the 3- and 5-year overall survival rates were 76% and 70%, respectively. Intensified ICT regimen could be a supplementary treatment option in the most advanced cases of LASCCA. Prospective randomized trials are needed to investigate this approach further. [ABSTRACT FROM AUTHOR]