Purpose: We report for the first time the activity and safety of Unithermia® (Elmedical Ltd, Hod-Hasharon, Israel), a novel device for administration of MMC-C with hyperthermia (HT), that employs conductive heating, in a series of non-grade 3 non-muscle-invasive bladder cancer (NMIBC) that failed Bacillus Calmette–Guerin (BCG). Methods: Patients with non-grade 3 NMIBC recurring after at least a full induction course of BCG were eligible for this phase I–II prospective single-arm study. Six weekly instillations with Unithermia® were scheduled following complete TUR. Primary end points were treatment safety and response rate (RR), and the latter defined as the absence of any unfavourable outcome at 12 months. Any grade 3 and/or muscle-invasive (T > 1) recurrence was considered disease progression. Kaplan–Meier estimation of the time to recurrence and progression, cancer-specific survival and overall survival was taken as secondary end points. Results: Thirty-four eligible patients entered the study between January 2009 and April 2011. RR was documented in 20/34 (59 %). Among the 14/34 (41 %) non-responders, four developed G3 disease, one developed carcinoma in situ, and one progressed to muscle-invasive bladder cancer, with an overall 18 % progression rate at 1 year. At a median follow-up of 41 months, recurrence and progression rates were 35.3 and 23.5 %, respectively. Toxicity did not go beyond grade 2 except in five cases. Conclusions: Initial experience with MMC-HT with Unithermia® showed an interesting activity and safety profile in non-grade 3 NMIBC recurring after BCG, suggesting a role as second-line therapy in this selected subgroup of NMIBC.