In an ongoing clinical trial, 100 patients with an unruptured ectopic pregnancy of 3.5 cm or less in greatest dimension were treated with an outpatient protocol of methotrexate and citrovorum factor chemotherapy. Methotrexate and citrovorum were given on alternating days until the hCG titer had decreased by 15% on 2 consecutive days. The patients ranged in age from 16-40 years, gravidity from 1-8, and parity from 0-5. Twenty-three patients had a previous ectopic pregnancy. Of the 100 patients, 96 (96%) received methotrexate/citrovorum as primary therapy and four (4%) were treated for persistent hCG titers after a conservative surgical procedure. The tubal pregnancies of patient nos. 1-50 were confirmed by laparoscopy, whereas patient nos. 51-100 were diagnosed according to a nonlaparoscopic algorithm. Four patients of 100 failed medical therapy and required surgery. Of these, one had an ectopic pregnancy with cardiac activity, one ruptured after intercourse, and the remaining two cases had no specific identifiable risk factors. Of the ectopic pregnancies with cardiac activity, 80% were successfully treated. Five patients (5%) had methotrexaterelated side effects, all after the fourth dose, but none required treatment for these side effects. Hysterosalpingograms done on 58 patients subsequently demonstrated tubal patency in 84.5% on the involved side. To date, 37 pregnancies have occurred in this group, of which 31 (89.2%) were intrauterine and four (10.8%) were recurrent ectopic pregnancies. We conclude that methotrexate/citrovorum is safe, effective, and helps to preserve reproductive performance when used as primary therapy for unruptured ectopic pregnancy and for treatment of persistent disease following a conservative surgical procedure.