Aim: To assess the long-term cost-effectiveness of an atrial fibrillation disease management program (i.e. the SAFETY program) from the Australian healthcare system perspective. Methods: A multistate Markov model was developed based on patient-level data from the SAFETY randomized controlled trial. Predicted long-term survival, dependent on hospital admission history, was estimated by extrapolating parametric survival models. Quality-adjusted life years (QALY) and life years (LY) were the primary and secondary outcome measures used to estimate the incremental costutility/effectiveness ratio (ICUR/ICER). Both deterministic and probabilistic sensitivity analyses (PSA) were undertaken. Results: The SAFETY program was associated with both higher costs ($94,953 vs. $78,433) and benefits [QALY (3.99 vs 3.60); LY (5.86 vs 5.24)], with an ICUR of $42,513/QALY or ICER of $26,356/LY, compared to standard care. Due to the extended survival, the SAFETY was associated with a greater number of hospitalizations (14.85 vs 11.65) and higher costs for medications ($25,084 vs $22,402) and outpatient care ($12,904 vs $11,524). The cost per hospitalization for an average length of stay, analytical time horizon, and cost of medication are key determinants of ICUR. The PSA showed that the intervention has a 70.4% probability of being cost-effective at a threshold of $50,000/QALY. Conclusions: The SAFETY program has a high probability of being cost-effective for patients with atrial fibrillation. It is associated with uncertainty that further research could potentially eliminate; implementation with further evidence collection is recommended.