Abstract Background There is no effective intravesical second-line therapy for non–muscle-invasive bladder cancer (NMIBC) when bacillus Calmette-Guérin (BCG) fails. Objective To compare disease-free survival time (DFS) between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following induction/maintenance BCG. Design, settings, and participants Open-label, phase III randomised controlled trial accrued across 14 centres between May 2010 and July 2013 (HYMN [ClinicalTrials.gov: NCT01094964]). Intervention Patients were randomly assigned (1:1) to RITE (60 min, 40 mg mitomycin-C, 42 ± 2 °C) or control following stratification for carcinoma in situ (CIS) status (present/absent), therapy history (failure of previous induction/maintenance BCG), and treatment centre. Outcome measurements and statistical analysis Primary outcome measures were DFS and complete response (CR) at 3 mo for the CIS at randomisation subgroup. Analysis was based on intention-to-treat. Results and limitations A total of 104 patients were randomised (48 RITE: 56 control). Median follow-up for the 31 patients without a DFS event was 36 mo. There was no significant difference in DFS between treatment arms (hazard ratio [HR] 1.33, 95% confidence interval [CI] 0.84–2.10, p = 0.23) or in 3-mo CR rate in CIS patients (n = 71; RITE: 30% vs control: 47%, p = 0.15). There was no significant difference in DFS between treatment arms in non-CIS patients (n = 33; RITE: 53% vs control: 24% at 24 mo, HR 0.50, 95% CI 0.22–1.17, p = 0.11). DFS was significantly lower in RITE than in control in CIS with/without papillary patients (n = 71; HR 2.06, 95% CI 1.17–3.62, p = 0.01; treatment-subgroup interaction p = 0.007). Disease progression was observed in four patients in each treatment arm. Adverse events and health-related quality of life between treatment arms were comparable. Conclusions DFS was similar between RITE and control. RITE may be a second-line therapy for non-CIS recurrence following BCG failure; however, confirmatory trials are needed. RITE patients with CIS with/without papillary had lower DFS than control. HYMN highlights the importance of the control arm when evaluating novel therapies. Patient summary This study did not show a difference in bladder cancer outcomes between microwave-heated chemotherapy and standard of care treatment. Papillary bladder lesions may benefit from microwave-heated chemotherapy treatment; however, more research is needed. Both treatments are similarly well tolerated. Take Home Message Radiofrequency-induced thermo-chemotherapy effect (RITE) had similar oncological outcomes as control. RITE-treated noncarcinoma in situ (CIS) patients reported nonsignificant better disease-free survival (DFS). RITE-treated CIS with/without papillary patients had significantly lower DFS. Control arm is essential when evaluating novel therapies. [ABSTRACT FROM AUTHOR]