OBJECTIVE We compared our institutional experience using 3D conformal radiation therapy (3DCRT) vs. IMRT (intensity-modulated radiation therapy) for anal cancer. METHODS We performed a single-institution retrospective review of all patients with squamous cell carcinoma anal cancer treated from September 2000 through September 2011, using definitive chemoradiation with curative intent. RESULTS This study included 89 consecutive patients (37 3DCRT, 52 IMRT). Median follow-up for all patients, IMRT patients alone, and CRT patients alone was 26.5 months (range, 3.5-133.6), 20 months (range, 3.5-125.5), and 61.9 months (range, 7.6-133.6), respectively. Three-year overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and colostomy-free survival (CFS) were 91.1%, 82.3%, 90.8%, and 91.3% in the IMRT cohort and 86.1%, 72.5%, 91.9%, and 93.7% in the 3DCRT group (all P > .1). More patients in the 3DCRT group required a treatment break (11 vs. 4; P = .006), although the difference in median treatment break duration was not significant (12.2 vs. 8.0 days; P = .35). Survival did not differ based on whether a treatment break was needed (all P > .1). Acute grade ≥3 nonhematologic toxicity was decreased in the IMRT cohort (21.1 vs. 59.5%; P < .0001). Acute grade ≥3 skin toxicity was worse in the 3DCRT group (P < .0001), whereas an improvement in late grade ≥3 gastrointestinal (GI) toxicity was observed in the IMRT patients (P = .012). CONCLUSIONS This study is the largest thus far to compare 3DCRT and IMRT for definitive treatment of anal cancer. Although long-term outcomes did not significantly differ based on RT technique, a marked decrease in adverse effects and the need for a treatment break was achieved with IMRT.