Repeated Spontaneous Abortions (RSA) is a major topic in reproductive medicine, affecting 1/20 pregnant woman worldwide. It has an adverse psychosocial impact in women and their families. The incidence of RSA is relatively high among the Malay population of Malaysia. Conventional hereditary thrombophilia factors have been generally ruled out. This study evaluated a new predisposition thrombophilia factor, M2/ANXA5 (RPRGL3). A total of 232 women who had experienced ≥ 2 unexplained RSA and 141 available male partners were recruited, with 360 healthy Malay and 166 parous female controls. The M2 carrier rate and RSA risks were determined in a) control and patient groups, b) clinically defined subgroups, and c) timing of pregnancy loss subgroups. Both male and female subjects had similar M2/ANXA5 allele frequencies. The carrier rate of M2/ANXA5 for the general Malay population was 42.2 % and 34.9 % for parous controls. These carrier rates compared to Malay RSA subjects resulted in an elevated RSA risk (OR = 1.53 and 1.97, respectively), specifically for early fetal losses (gestational weeks ≤ 15). Moreover, exceeding copy numbers of M2/ANXA5 alleles seemed to contribute a higher risk in RSA couples especially when both partners were M2 carriers. This study confirmed the proposed role of M2/ANXA5 as a genetically associated thrombophilia predisposition factor for RSA among ethnic Malay of Malaysia.