Objective. To compare the success rates of single and multiple dose methotrexate protocols for the treatment of unruptured tubal ectopic pregnancy. Design. Prospective randomized controlled trial. Setting. Maternity and teaching hospital in Turkey. Population. One hundred twenty women treated with methotrexate therapy for unruptured tubal ectopic pregnancy. Methods. Sixty-two women received a single dose and 58 received a multiple dose methotrexate regimen. Main outcome measures. Success rate of methotrexate therapy (women successfully treated with one injection and women who completed four doses). Results. In the single dose group, treatment was considered successful in 50 women (80.6%), whereas in the multiple dose group, 52 women (89.7%) responded to treatment (p = 0.21; OR 0.90, 95% CI 0.77-1.05). The average number of days required for human chorionic gonadotropin (hCG) levels to fall below 5 mU/mL was longer in the single dose (22.3 +/- 7.6) compared with the multiple dose group (18.3 +/- 10.7) (p = 0.03). In the single dose group fewer or 17 women (24.7%) experienced side-effects compared to 28 (48.3%) of those who had multiple doses (p = 0.02, OR 0.57, 95% CI 0.35-0.92). Conclusion. A multiple dose methotrexate regimen for the treatment of unruptured tubal ectopic pregnancy is not more effective than a single dose one. In addition, multiple doses may cause more side-effects, but the time for hCG levels to fall below 5 mU/mL is shorter.