Membranous nephropathy is an autoimmune disease and one of the most common causes of nephrotic syndrome in adults. The incidence of membranous nephropathy is 1.2 in 100,000 persons per year worldwide. Approximately 80% of patients with membranous nephropathy have a classification of primary (or idiopathic) membranous nephropathy. The treatment goal of patients with primary membranous nephropathy is to induce remission. Current treatment options include calcineurin inhibitors (cyclosporine and tacrolimus), cyclophosphamide, and rituximab. Rituximab is not approved for the indication of primary membranous nephropathy in Canada. This review aimed to evaluate the evidence on the use of rituximab compared to cyclophosphamide, tacrolimus, and cyclosporine in adult patients with primary membranous nephropathy. A systematic review of the efficacy and safety of rituximab versus cyclosporine, tacrolimus, or cyclophosphamide was conducted with 18 included randomized controlled trials. A network meta-analysis of 11 of the 18 included randomized controlled trials was uninformative due to the small number of studies, the heterogeneity in the studies, and unreliable point estimates and wide credible intervals obtained with the network meta-analysis. Due to the uninformative nature of the network meta-analysis, a narrative analysis was conducted of the head-to-head trials of rituximab. Two randomized controlled trials showed no evidence of a difference between rituximab and cyclophosphamide, whereas rituximab resulted in a better response rate (complete remission and the composite outcome of partial or complete remission) at 24 months compared with cyclosporine. There were no head-to-head trials comparing rituximab with tacrolimus. Given the small network of studies, the heterogeneity in the included studies, and the limited information provided by the network meta-analysis and the pairwise comparisons of the MENTOR and RI-CYCLO trials, CADTH was unable to conduct an informative economic evaluation. Further, in addition to the clinical evidence gaps, there were also issues identifying information to inform key parameters to address the policy question of interest to decision-makers. Given the limitations associated with the clinical evidence and absence of evidence to inform key model parameters, an economic evaluation would not be able to quantify all relevant incremental costs and effects of using rituximab over the currently used alternatives.