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Simple Summary Concurrent chemo-radiotherapy is the standard treatment in anal cancer. Intensity-modulated radiotherapy (IMRT) was proved to reduce severe, acute and late toxicities. Moreover, IMRT techniques allow for the planning and delivery of a simultaneous integrated boost (SIB), with a differential dose per fraction given to selected sub-regions during the same treatment session. This boost modality provides the chance to employ a dose-painted approach with a reduction in overall treatment time that could result in a potential clinical advantage. Since a large variability in dose prescription to the primary tumor and elective or involved lymph nodes can be found in available guidelines and clinical practice, a multicenter analysis was conducted to evaluate the pattern of care and the impact of radiotherapy parameters on clinical outcomes for anal cancer patients treated with IMRT techniques within a national cohort. Abstract A multi-institutional retrospective study was conducted to evaluate the pattern of care and clinical outcomes of anal cancer patients treated with intensity-modulated radiotherapy (IMRT) techniques. In a cohort of 987 patients, the clinical complete response (CR) rate (beyond 6 months) was 90.6%. The 3-year local control (LC) rate was 85.8% (95% CI: 84.4–87.2), and the 3-year colostomy-free survival (CFS) rate was 77.9% (95% CI: 76.1–79.8). Three-year progression-free survival (PFS) and overall survival (OS) rates were 80.2% and 88.1% (95% CI: 78.8–89.4) (95% CI: 78.5–81.9), respectively. Histological grade 3 and nodal involvement were associated with lower CR (p = 0.030 and p = 0.004, respectively). A statistically significant association was found between advanced stage and nodal involvement, and LC, CFS, PFS, OS and event-free survival (EFS). Overall treatment time (OTT) ≥45 days showed a trend for a lower PFS (p = 0.050) and was significantly associated with lower EFS (p = 0.030) and histological grade 3 with a lower LC (p = 0.025). No statistically significant association was found between total dose, dose/fraction and/or boost modality and clinical outcomes. This analysis reports excellent clinical results and a mild toxicity profile, confirming IMRT techniques as standard of care for the curative treatment of anal cancer patients. Lymph node involvement and histological grade have been confirmed as the most important negative prognostic factors.