Background: One in seven women will develop breast cancer, making it the most common female cancer worldwide. Consequently, breast cancer-related treatment, including breast reconstruction, impacts societal costs. Autologous fat transfer (AFT) is a relatively new breast reconstruction technique; however, several surgeries are necessary. This study investigates if AFT with pre-expansion is more cost-effective than implant-based reconstruction (IBR). Methods: Seven centers assigned patients randomly from 2015 to 2021 to evaluate costs and EQ-5D-5L quality-adjusted life years (QALY) of AFT vs. IBR at 12 months postoperative. Costs were calculated, including direct costs related to treatment and PROductivity and DISease Questionnaire, to estimate productivity loss (indirect costs). Sensitivity analyses were performed for 10- and 30 years to estimate costs for patients replacing or explanting their breast implants over time. Results: A total of 152 women, of which 91 received AFT (mean age 49.3) and 80 IBR (mean age 49.1). The mean EQ-5D-5L QALY in the AFT group was 0.83, compared with the IBR group of 0.79. Total costs for AFT at 12 months postoperative were higher than IBR (incremental cost: €6763.59). Sensitivity analyses for 10- and 30-year scenarios showed mean incremental costs of respectively €2586.56 and €680.22. Conclusion: Mean EQ-5D-5L QALY and costs were higher for AFT over the first year after reconstruction. However, these costs were low; therefore, AFT was estimated to be more cost-effective over the 10- and 30-year period since no additional surgeries are necessary for this group. Larger cohorts are required to confirm AFT is more cost-effective in the long term.