Background and objective: Pregnancy is similar to allogeneic transplantation. Eighty percent of unexplained recurrent spontaneous abortions (URSA) relate to disturbances of immune regulation. Cyclosporin A (CsA) is a immunosuppressant widely used after organ transplantation and to treat autoimmune disease. Animal studies show that low dose of CsA could induce maternal-fetal immunity tolerance while enhance trophoblast invasion. So far no clinical trial reported on the effect and safety of cyclosporin A treatment for URSA has been published. The objective of this study was to explore the effect, safety, and mechanism of low-dose CsA treatment in human patients in order to find a novel therapy to treat URSA. Materials and Methods: Eighty-six patients with eligible URSA treated at the clinic of the present hospital were included in this study from December 2009 to December 2012. The research was approved by the Ethics committee. Through a clinical study with prospective non-randomized controlled trials, the patients were divided into CsA treatment group (n = 66 cases) and in control group (n = 20 cases) based on the patients’ choice. Both groups started treatment as soon as the pregnancy test was positive. Patients in the treatment group were treated with oral CsA 100 mg/day for 30 days. Patients in the control group were treated with progesterone 20 mg im per day until 12 weeks of gestation. Cytoimmunology test of CD3, CD4, CD8, CD4/8, CD4/25, CD19/21, and Th/Ts were examined before and after the treatment in both groups. Clinical consequences of mothers and fetuses were followed up and recorded. Live birth rate and cytoimmunology markers and their change before and after the treatment were analyzed and compared between the two groups. Results: The live birth rate was significantly higher in study group (41/66, 62.1%) than in the control group (6/20, 30.0%) (p < 0.001). There was no obvious side effect and adverse consequence in the pregnancy women. No IUGR or birth defect was observed in fetus in this study. After CsA treatment, CD3 level in maternal blood was higher in successful group than abortion group but CD8 level was decreased after CsA treatment. Conclusions: Low-dose CsA treatment increases live birth rate of unexplained recurrent abortion. No maternal-fetal adverse consequence was observed in this study and it is safe in clinic use. The mechanism of CsA therapy may be related to immune regulation which may favor the success of pregnancy.