OBJECTIVES: Evaluate costs and benefits of rituximab in combination with cyclophosphamide/vincristine/prednisolone chemotherapy regimen (R-CVP) versus CVP alone in previously untreated patients with indolent non-Hodgkin lymphoma (NHL). METHODS: Cost-effectiveness (Life Years Gained - LYG) and cost-utility analysis (Quality Adjusted Life years – QALYs) were performed for a time horizon of 10 years according to a Markov economic model with three health states (“progression free survival”, “progression” and “death”) and monthly cycles. Data from a phase III clinical trial (Marcus R. et al 2007) was used and expanded in the model to include unpublished 53-month median follow-up data. Survival after first-line therapy was estimated from the Scotland and Newcastle Lymphoma Group registry data and utilities were derived from a UK study. Resource consumption was estimated by a Portuguese expert panel. Costs were calculated from the Portuguese Health System perspective through official data with prices updated to 2010. Only direct medical costs were considered. Costs and consequences were discounted at 5% per annum. Deterministic and probabilistic sensitivity analyses were performed around assumptions on the time horizon, costs, utilities and excess mortality rate due to progression applied in the base-case analysis. RESULTS: The 10-year base-case analysis showed a lower total cost per patient with CVP alone (€88,373) versus R-CVP (€89,899). Life expectancy and quality-adjusted life expectancy per patient were higher with R-CVP (6.361 and 4.166, respectively) versus CVP alone (5.557 and 3.438, respectively), representing increases of 0.804 in LYG and 0.728 in QALYs gained. The incremental cost per QALY gained was €2097 (base-case) and €6006 considering a lifetime horizon (25 years). The sensitivity analyses confirmed the robustness of the model. CONCLUSIONS: This study demonstrates that the combination R-CVP in previously untreated NHL patients improves life expectancy and is a cost-effective alternative to CVP in Portugal.