BACKGROUND: The TROG 99.03 trial demonstrated improved progression-free survival for patients with early-stage follicular lymphoma (FL) treated with systemic therapy using rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) after involved-field radiotherapy (RT) versus RT. As systemic therapy was associated with more acute toxicity, the possibility of long-term toxicity, and no survival benefit yet, the cost-effectiveness of RT+R-CVP is important. AIM: We performed a cost-effectiveness analysis of RT (reference), RT+CVP, and RT+R-CVP from the TROG 99.03 trial. METHODS: We constructed a Markov model (15-year horizon) to compare treatments: RT (reference), RT+CVP and RT+R-CVP from the 150 patients in the TROG 99.03 trial. Median follow-up was 11.3 years (range: 4.4-17.8). Lifetime direct health care costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. Australian dollars AUD$50,000 was defined as the proposed willingness-to-pay threshold (WTP). RESULTS: RT+R-CVP was associated with an improvement of 0.711 QALYs compared to RT, 0.532 QALYs compared to RT+CVP, and was the dominant strategy. The costs of adverse events or retreatment for relapses or transformation had a minimal influence on the ICERs. Sensitivity analyses resulted in ICER values below the WTP with RT+R-CVP remaining the dominant strategy. CONCLUSION: RT+R-CVP is clearly cost-effective and was the dominant strategy in early-stage FL compared to RT or RT+CVP as it delivers superior outcomes at a lower cost from the Australian tax-payer's perspective. TRIAL REGISTRATION: The authors have confirmed clinical trial registration is not needed for this submission.