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Objective: To evaluate whether superovulation improves fecundity in women undergoing therapeutic donor insemination (TDI)., Design: Retrospective cohort study., Setting: University-affiliated fertility clinic., Patient(s): Healthy women aged 23-45 years with no history of or risk factors for infertility who underwent 152 medicated and 104 unmedicated TDI cycles from 2013 to 2018., Intervention: Unmedicated TDI versus use of medication in a TDI cycle (clomiphene citrate or letrozole)., Main Outcome Measure(s): Cumulative probability of pregnancy in six TDI cycles., Result(s): In adjusted all-cycle analysis, medicated TDI cycles were less likely to result in pregnancy compared with unmedicated cycles. The incidence of twins was 23% in the medicated group and 0% in the unmedicated group. Medicated cycles were less likely to result in pregnancy in women younger than 40 years or with an antimüllerian hormone (AMH) level >1.2. After three cycles not resulting in pregnancy, the only women who conceived were those who crossed over from an unmedicated to a medicated cycle (12% vs. 0%)., Conclusion(s): Patients undergoing unmedicated TDI cycles had higher fecundity and no incidence of twin gestations. Older women, those with low AMH, and those who fail to conceive after three unmedicated cycles may benefit from medication., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)