Background: The use of serial quantitative beta-human chorionic gonadotropin (β-HCG) with transvaginal ultrasound to enhance early diagnosis of ectopic pregnancy (EP) improves options for conservative treatment with methotrexate (MTX). The aim of this study was to evaluate the outcome of unruptured EP treated with a single dose of intramuscular MTX injection.Methods: This clinical trial included 41 EP patients with specific inclusion criteria for medical treatment. For each patient, MTX (50 mg/ml) was administered intramuscularly and a repeat dose was given if the weekly decrease in the level of β-HCG was less than 15%. The therapy was considered successful if the level of β-HCG fell below 10 mIU/cc without surgical intervention.Results: Overall, 78% of the patients were successfully treated, among whom 18.7% received second doses of MTX. Of the patients who were successfully treated, 60% presented with vaginal bleeding without pelvic pain; however, of those patients in whom the treatment failed, 88% presented with pelvic pain together with vaginal bleeding. Furthermore, the presence of free peritoneal fluid on vaginal ultrasound was a significant predictor of treatment failure (p<0.005). There was no relation between the women's age, gravidity or parity, the size of the conceptus, gestational age, pretreatment serum β-HCG titer, endometrial thickness on vaginal ultrasound and the efficacy of treatment.Conclusions: With a reasonably high success rate, we found systemic single-dose MTX treatment to be a safe, conservative therapy for EP. However, when free peritoneal fluid is noted upon transvaginal ultrasound or when the patient presents with pain, the threshold for surgical intervention may be lower.