Cisplatin-based radio-chemotherapy is an effective alternative to cystectomy. The position of cisplatin has been challenged by novel drugs, while altered radiotherapy fractionation is also tested against conventional radiotherapy (RT). This study focuses on liposomal doxorubicin (LDox) in combination with an aggressive radiotherapy scheme (HypoARC). Eighty-two bladder cancer patients were treated with hypofractionated/accelerated RT (14×2.7 Gy to the pelvis and 15×3.4 Gy to the bladder, within 19 days), supported with amifostine (0-1,000 mg sc.). Forty-one out of 82 patients received concurrently LDox (20 mg/m2 for 3 bi-weekly cycles). LDox was free of haematological toxicity, erythordysestesia grade 1 being the only side effect noted in 5/41 patients. Although the incidence of early toxicities did not increase with LDox, delays of radiotherapy were increased (P=0.16). Amifostine significantly protected patients against toxicities and delays. There were no severe late complications recorded. Complete response rate was similar in both groups (85.4 vs. 87.8%). The 3-year local relapse-free survival was better in patients receiving LDox, but at a non-statistical level (64 vs. 47%; P=0.59). The 3-year survival rate was significantly improved in T2-4 stage patients receiving LDox (72.1 vs. 58.7%; P=0.04). Multivariate analysis did not identify any independent prognostic variables of relapse or death events. LDox is a well-tolerated drug during pelvic radiotherapy. Although its efficacy in terms of bladder tumour control rates could not be substantiated due to the high efficacy of the HypoARC regimen applied, survival was improved suggesting either a spatial co-operation or a radio-sensitization of pelvic in-field subclinical disease.