To evaluate toxicity and cosmetic outcome (CO) in breast cancer survivors treated with three-dimensional conformal radiotherapy with a hypofractionated, simultaneous integrated boost (3D-CRT-SIB) and to identify risk factors for toxicity, with special focus on the impact of age. Included were 940 consecutive disease-free patients treated for breast cancer (Stage 0–III) with 3D-CRT-SIB, after breast-conserving surgery, from 2005 to 2010. Physician-rated toxicity (Common Terminology Criteria for Adverse Events version 3.0) and CO were prospectively assessed during yearly follow-up, up to 5 years after radiotherapy. Multivariate logistic regression analyses using a bootstrapping method were performed. At 3 years, toxicity scores of 436 patients were available. Grade ≥2 fibrosis in the boost area was observed in 8.5%, non-boost fibrosis in 49.4%, pain to the chest wall in 6.7%, and fair/poor CO in 39.7% of cases. Radiotherapy before chemotherapy was significantly associated with grade ≥2 boost fibrosis at 3 years (odds ratio OR 2.8, 95% confidence interval CI 1.3–6.0). Non-boost fibrosis was associated with re-resection (OR 2.2, 95% CI 1.2–4.0) and larger tumors (OR 1.1, 95% CI 1.0–1.1). At 1 year, chest wall pain was significantly associated with high boost dosage (OR 2.1, 95% CI 1.2–3.7) and younger age (OR 0.4, 95% CI 0.2–0.7). A fair/poor CO was observed more often after re-resection (OR 4.5, 95% CI 2.4–8.5), after regional radiotherapy (OR 2.9, 95% CI 1.2–7.1), and in larger tumors (OR 1.1, 95% CI 1.0–1.1). Toxicity and CO are not impaired after 3D-CRT-SIB. Fibrosis was not significantly associated with radiotherapy parameters. Independent risk factors for fibrosis were chemotherapy after radiotherapy, re-resection, and larger tumor size. Re-resection was most predictive for worse CO. Age had an impact on chest wall pain occurrence.