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Objective The aim of the study was to compare the efficacy of two methods of administering methotrexate in the treatment of ectopic pregnancy (EP) - multiple-dose methotrexate intramuscular injection and single-dose methotrexate intramuscular injection - in a prospective randomized study. Data analysis Electronic medical research databases were searched from 1982 or from the starting date of each database. The search was performed on 1 March 2013 and included ahead-published printed articles without language restrictions. Study selection The initial search presented 250 articles, of which 30 met the inclusion criteria. The articles were previous trials on methotrexate therapy in the treatment of EP as well as current therapies previously trialed and potential therapies for the near future. Data extraction Studies that had obtained ethical approval, that followed a prospective randomized design, with specific eligibility criteria, used appropriate controls, and with adequate follow-up and defined outcome measures were selected. Data synthesis Although heterogeneity existed in follow-up periods and in reported outcome measures, it was possible to pool the data and perform comparisons by statistical review. Recent findings Early diagnosis of EP allows a conservative medical approach with methotrexate, which is considered the treatment of choice over surgical intervention. This includes the use of methotrexate in a single-dose injection or multiple-dose injections as comparable protocols for treatment of EP. Conclusion Methotrexate is a reliable method for treatment of early unruptured EP either by single-dose methotrexate intramuscular injection or multiple-dose methotrexate intramuscular injection. There are no significant differences in primary treatment success. Single-dose injections have lower side effects compared with multiple-dose injections.