Background Consensus is lacking regarding the optimal salvage therapy for patients with follicular lymphoma who relapse after or are refractory to immunochemotherapy. Methods This phase II trial evaluated the efficacy and safety of response‐adapted therapy with rituximab, bendamustine, mitoxantrone, and dexamethasone (RBMD) in follicular lymphoma patients who relapsed after or were refractory to first‐line immunochemotherapy. Sixty patients received three treatment cycles, and depending on their response received an additional one (complete/unconfirmed complete response) or three (partial response) cycles. Patients who responded to induction received rituximab maintenance therapy for 2 years. Results Thirty‐three (55%) and 42 (70%) patients achieved complete/unconfirmed complete response after three cycles and on completing induction therapy (4‐6 cycles), respectively (final overall response rate, 88.3%). Median progression‐free survival was 56.4 months (median follow‐up, 28.3 months; 95% CI, 15.6‐51.2). Overall survival was not reached. Progression‐free survival did not differ between patients who received four vs six cycles (P = .6665), nor between patients who did/did not receive rituximab maintenance after first‐line therapy (P = .5790). Median progression‐free survival in the 10 refractory patients was 25.5 months (95% CI, 0.6‐N/A) and was longer in patients who had shown progression of disease after 24 months of first‐line therapy (median, 56.4 months; 95% CI, 19.8‐56.4) than in those who showed early progression (median, 42.31 months; 95% CI, 24.41–NA) (P = .4258). Thirty‐six (60%) patients had grade 3/4 neutropenia. Grade 3/4 febrile neutropenia and infection were recorded during induction (4/60 6.7% and 5/60 8.3% patients, respectively) and maintenance (2/43 4.5% and 4/43 9.1% patients, respectively). Conclusions This response‐adapted treatment with RBMD followed by rituximab maintenance is an effective and well‐tolerated salvage treatment for relapsed/refractory follicular lymphoma following first‐line immunochemotherapy. Clinical trial registration ClinicalTrials.gov # NCT01133158. RBMD using a response‐adapted strategy followed by rituximab maintenance is an effective and safe salvage treatment for relapsed/refractory follicular lymphoma following first‐line immunochemotherapy, thereby improving tolerability without compromising efficacy.