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Objective: To evaluate potential risk factors at admission for failed single-dose methotrexate injection in women with ectopic pregnancy., Methods: File review of a tertiary medical center in Israel yielded 102 consecutive patients with ectopic pregnancy initially treated with single-dose methotrexate. Overall successful treatment was defined as normalization of human chorionic gonadotropin (hCG) levels after the first or second injection., Results: The mean pretreatment hCG level for the whole cohort was 2350 ± 2955 mIU/mL (median, 1187 mIU/mL; 90th percentile, 5000 mIU/mL). Resolution of ectopic pregnancy was achieved after a single injection in 76/102 (74.5%) women and after a second dose in 16/21 (76.2%) women. The remaining 10 (9.8%) patients were treated surgically after the first (5/76) or the second (5/26) dose. The overall success rate for methotrexate treatment was 90.2%. On multivariate stepwise logistic analysis, fetal cardiac activity was an independent predictor of a failed first methotrexate injection, and presence of a yolk sac and mass size were independent predictors of overall methotrexate failure and need for secondary surgery., Conclusion: In patients with ectopic pregnancy and relatively low levels of serum hCG, the most important predictors of overall failure of methotrexate injection were the presence of a yolk sac and mass size., (Copyright © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)