The authors present a series of 643 patients with ectopic pregnancy who were treated with either multiple (n = 97) or single doses (n = 546) of methotrexate. All participants were hemodynamically stable, did not have freeperitoneal fluid outside the pelvic cavity, did not desire surgical therapy, and agreed to appropriate follow up. The maximum size of ectopic pregnancy eligible for multidose methotrexate was increased from 3.0 cm to 3.5 cm during the course of the study. Similarly, single-dose methotrexate was initially given to women with an ectopic pregnancy ≤3.5 cm in diameter. After 200 patients, the maximum size was increased to 4.0 cm if there was no cardiac activity. If cardiac activity was detected, a maximum pregnancy size of 3.5 cm was permitted for methotrexate therapy. Multidose methotrexate was given intramuscularly on alternate days in dosages equal to 1.0 mg per kilogram of body weight. Citrovorum rescue factor was administered on the day after a methotrexate injection. Treatment was discontinued after a 15% decline in hCG titers on 2 consecutive days. If levels plateaued or rose on 2 consecutive days, treatment was resumed. Single doses of methotrexate were given intramuscularly in a dosage equal to 50 mg/m 2 body surface area, which was calculated from a nomogram using height and actual body weight. The dose was repeated in 7 days if hCG titers did not drop by at least 15% between day 4 and day 7, and weekly until hCG levels fell to ≤15 mIU/mL, which was considered the level of treatment success. Patients who received multidose and single-dose therapy had similar rates of success (95% and 90%, respectively; P =.18) They also had similar hCG levels, progesterone levels, instances of previous ectopic pregnancy, days of treatment, gestational age, ectopic size, ectopic volume, and ectopic mass volume. Significant differences were seen between multidose and single-dose patients in patient weight (146 lbs vs 159 lbs; P =.006), ectopic cardiac activity (3.1% vs 10.3%), and total number of methotrexate doses. Success was achieved with a single dose of methotrexate in 17.5% of the multidose group and 76% of the single-dose group. In 35.2% and 20.7%, respectively, 2 doses were required for success. Three and 4 doses were required in 24.7% and 2.9%, and 22.7% and 0.4%, respectively. When analyzed on an intent-to-treat basis, success rates were 95% for multidose patients and 89% for single-dose patients (P =.0).