ObjectiveTo investigate the optimal route of progesterone administration for luteal phase support in a frozen embryo transfer.DesignSystematic review.PatientsWomen undergoing frozen embryo transfer (FET).InterventionsWe conducted an extensive database search of Medline (PubMed), Embase, Web of Science, and Cochrane Trials Register using relevant keywords and their combinations to find randomized controlled trials (RCTs) comparing the routes (i.e., oral, vaginal, intramuscular) of progesterone administration for luteal phase support (LPS) in artificial FET.Main outcome measuresClinical pregnancy, live birth, miscarriage.ResultsFour RCTs with 3245 participants undergoing artificial endometrial preparation (EP) cycles during FET were found to be eligible. Four trials compared vaginal progesterone with intramuscular progesterone and two trials compared vaginal progesterone with oral progesterone. One study favored of vaginal versus oral progesterone for clinical pregnancy rates (RR 0.45, 95% CI 0.22–0.92) and other study favored intramuscular versus vaginal progesterone for clinical pregnancy rates (RR 1.46, 95% CI 1.21–1.76) and live birth rates (RR 1.62, 95% CI 1.28–2.05). Tabulation of overall evidence strength assessment showed low-quality evidence on the basis that for each outcome-comparison pair, there were deficiencies in either directness of outcome measurement or study quality.ConclusionThere was little consensus and evidence was heterogeneous on the optimal route of administration of progesterone for LPS during FET in artificial EP cycles. This warrants more trials, indirect comparisons, and network meta-analyses.PROPERO NoCRD42021251017.