Bendamustine has demonstrated clinical activity and a favorable safety profile as monotherapy or in combination with rituximab in lymphoid malignancies. As interventional trials do not always reflect clinical reality, we were interested in the treatment modalities and the outcome of bendamustine-based first-line therapy in patients with advanced indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL) in routine practice. Between April 2010 and October 2011, 324 patients were enrolled in a prospective non-interventional multicenter study. Choice of the bendamustine regimen was at the treating physician's discretion. Effectiveness was assessed by best response. Mean age at onset of therapy was 69 years. The majority (94 %) of the patients was treated with bendamustine in combination with rituximab at a median bendamustine dose of 177 mg/m(2) per cycle. Most often, bendamustine was administered on days 1 and 2 (87 %) at 4-week intervals over a median of 6 cycles. Two hundred eighty-one patients qualified for evaluation of response. The overall response rate was 86 % (complete response 43 %, partial response 43 %, stable disease 10 %, progressive disease 4 %). Side effects of all grades were documented for 161 of the 323 patients (50 %), most frequently affecting blood/bone marrow (35 %). Fifty-four (17 %) patients experienced side effects of grade 3 (15 %) or grade 4 (2 %), and two patients grade 5 toxicities. Bendamustine-based first-line treatment of patients with advanced indolent NHL and MCL in clinical routine practice was assessed as effective and well tolerated in our study. Response was comparable to results from interventional clinical trials.