Background:Abortion is one of the prevalent problems of obstetrics throughout the world. Standard and usual method for pregnancy termination at first trimester is surgery (curettage). Another effective pregnancy termination method at first trimester is the use of medical treatments. The aim of this study is to compare the efficacy of misoprostol alone or in combination with methotrexate for termination of pregnancy at first trimester. Methods:This study is a Randomized Clinical Trial. A total of 200 pregnant women at first trimester of pregnancy were randomly divided into two groups for termination of pregnancy. First group received misoprostol alone (800 mg, vaginal, one or two dose) and second group received misoprostol in combination with methotrexate (50 mg/m2/IM and 800 mg vaginal misoprostol in one or two dose was administered 72 hours later). Sonography was administered at seventh day for both groups and curettage was done if pregnancy was continued or if fetus residual was existed. Findings:Successful abortion rate was 83% at first group and 81% at second group. There was a significant relation between dose of misoprostol and need for curettage and a significant relation between kind of pregnancy and need for curettage in both groups (P = 0.001 and P < 0.001, respectively). But there was no significant relation between gestational age and number of drug declaring in both groups (P = 0.934). No adverse events or side effects were reported side-effects were reported with the use of misoprostol and methotrexate.    Conclusion:Pregnancy termination with medical method along with misoprostol alone or in combination with methotrexate is safe and cost effective. Key words: Missed abortion, misoprostol, methotrexate, premature medical abortion