OBJECTIVE: To determine whether in vitro fertilization with preimplantation genetic screening (IVF/PGS) is cost effective compared with expectant management in achieving live birth for patients with unexplained recurrent pregnancy loss (RPL). DESIGN: Decision analytic model comparing costs and clinical outcomes. SETTING: Academic recurrent pregnancy loss programs. PATIENT(S): Women with unexplained RPL. INTERVENTION(S): IVF/PGS with 24-chromosome screening and expectant management. MAIN OUTCOMES MEASURE(S): Cost per live birth. RESULT(S): The IVF/PGS strategy had a live-birth rate of 53% and a clinical miscarriage rate of 7%. Expectant management had a live-birth rate of 67% and clinical miscarriage rate of 24%. The IVF/PGS strategy was 100-fold more expensive, costing $45,300 per live birth compared with $418 per live birth with expectant management. CONCLUSION(S): In this model, IVF/PGS was not a cost-effective strategy for increasing live birth. Furthermore, the live-birth rate with IVF/PGS needs to be 91% to be cost effective compared with expectant management.