OBJECTIVE: To analyze X inactivation in women with recurrent miscarriage to estimate whether skewed X inactivation is associated with recurrent miscarriage and whether it predicts next pregnancy outcomes. METHODS: A multicenter study was performed. A power calculation determined that 101 patients were needed to detect a difference in skewed X inactivation between patients and controls. Patients were entered into a prospective trial of mononuclear-cell immunotherapy and subsequently tested for skewed X inactivation. Age-matched controls had one live birth and no prior miscarriages. Results from our X inactivation assay were compared with those from an independent genetics laboratory. RESULTS: Greater than 75% skewing was seen in 22.6% of patients and 26.5% controls (P = .52). Greater than 90% skewing was seen in 6.6% of patients and 3.9% of controls (P = .77). There were 19.8% of primary aborters and 32% of secondary aborters with greater than 75% skewed X inactivation (P = .38). There were 4.9% of primary aborters and 12.0% of secondary aborters with greater than 90% skewed X inactivation (P = .27) Neither greater than 75% nor greater than 90% skewed X inactivation impacted next pregnancy outcomes (odds ratios = 0.87 [95% confidence interval (CI) 0.34, 2.3] and 1.4 [95% CI 0.27, 7.5], respectively). Results of the exchange of samples with an independent laboratory were highly correlated (α = 0.987, P < .001, coefficient of variation = 5.5%). CONCLUSION: Skewed X chromosome inactivation is not associated with recurrent miscarriage. A patient's X chromosome inactivation status does not predict next pregnancy outcome. Our assay correlates with another experienced laboratory.