Purpose Whole-breast irradiation after conservative surgery is the standard treatment for early breast cancer. The purpose of this study is to report the late toxicity, cosmetic result, and disease control in a group of patients treated with hypofractionated radiotherapy (RT) comparing results with retrospective data of a control group who underwent conventional RT. Methods From 2006 to 2008, 85 patients were treated with hypofractionated schedule to dose of 45 Gy, 2.25 Gy/fr, followed by a boost. We evaluated late toxicity, cosmetic result, and disease control. The data were compared to a control group of 70 patients who underwent conventional RT before 2006. Results At 8 years of follow-up, the cumulative incidence of late skin toxicity was 6.2 in the hypofractionated RT group and 7.5 in the standard RT group (p = 0.94). The cumulative incidence of late subcutaneous tissue toxicity was 11.6 in the hypofractionated RT group and 18.7 in the standard RT group (p = 0.23). Cosmetic outcome was rated as excellent or good in 84/85 patients of the hypofractionated RT group and in 68/70 patients of the conventional RT group (p = 0.7). No statistically significant differences were found in terms of local control (p = 0.05), disease-free survival (p = 0.06), or overall survival (p = 0.17) between the 2 groups. Conclusions The present analysis, focused on long-term effects, disease control, and survival, confirms, in a daily practice setting, the low incidence of skin atrophy and fibrosis, the satisfactory cosmetic outcome, and the high grade of local and distant disease control with hypofractionated schedule.