Comparative data on immunochemotherapy regimens for Waldenström macroglobulinaemia/lymphoplasmacytic lymphoma (WM/LPL) are lacking. We analysed overall survival (OS), risk of hospitalizations, transfusions and plasmapheresis in a population‐based cohort of patients ≥65 years old initiating WM/LPL therapy in 1999–2013. To minimize bias, we applied a propensity score‐based causal inference method. We conducted three analyses of: patients treated with or without rituximab, patients treated with rituximab monotherapy or with combination immunochemotherapy, and regimens based on classic purine analogues or alkylators. Among 1310 patients, 78·5% received rituximab. Patients who received rituximab had significantly better OS [hazard ratio (HR) 0·62, 95% confidence interval (CI) 0·55–0·71] and lower risk of transfusions (risk difference −3·3%, 95% CI −6·3 to −0·3) than those who did not, without a significant difference in hospitalizations or plasmapheresis. We observed no significant difference in OS (HR 0·91, 95% CI 0·79–1·04) between rituximab monotherapy and combination immunochemotherapy, but toxicity outcomes were lower with rituximab alone. Neither survival (HR 1·10, 95%CI 0·92–1·32) nor toxicity outcomes differed significantly between regimens based on purine analogues or alkylators. The survival advantage strongly supports rituximab as part of upfront therapy for WM/LPL, whereas regimens with either purine analogues or alkylating agents result in similar outcomes.