For a study, researchers sought to assess the long-term QOL of patients with anal cancer after chemoradiation. This study used data from a prospective study of anal cancer patients who received chemoradiation between 2008 and 2013. Patients with anal cancer who received image-guided intensity-modulated radiation therapy were included in the study. English-speaking patients completed cancer-specific (C30) and site-specific (CR29) QOL questionnaires at the start of treatment, at the end of radiation, at 3 and 6 months, and then annually. Long-term QOL was assessed clinically (a difference in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing subscale scores at 1, 2, and 3 years to baseline scores. A subanalysis compared patients who received radiation doses ranging from 45 to 54 Gy to those who received 63 Gy. There were 96 patients in total (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decrease at the end of treatment, followed by improvement 3 months later. Long-term statistically significant improvements in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss were observed, while impotence worsened statistically and clinically. A higher radiation dose (63 Gy) did not result in significantly worse QOL. The single-institution, single-arm study design, and lack of dose reconstruction were all limitations (i.e., analyses were based on prescribed, rather than delivered, dose). Patients with anal cancer who received chemoradiation reported a return to baseline levels of overall QOL. Specific symptoms persisted, emphasizing the importance of addressing and managing chemoradiation-induced symptoms both during treatment and in the long run.