Conventionally, the zygosity of twins into monozygotic (MZ) and dizygotic (DZ) is determined by utilizing several blood groups or other genetic markers. Existence of many blood groups or other genetic markers raises the crucial problem of choosing minimum number of blood groups and applying them in a sequence with minimum cost offering maximum effectiveness in classifying the twins by zygosity. In this note, a statistical approach to this problem is made and a solution provided. The efficient sequential search procedure utilizing the gene frequency of four blood groups from the German population of Nordrhein-Westfalen province and applying the results to a twin set of 72 pairs (32 MZ and 40 DZ) of the same population indicates that efficient sequences with 3 and 4 blood groups are AB0→P→Rh and AB0→P→Rh→MNSs, respectively. Further, it is understood that the efficient sequence for zygosity determination will be differing from population to population. As gene frequencies of blood systems differ in the various populations, this will effect the probability that a DZ twin pairs is concordant for a specific marker. Moreover, the relative cost may also turn out to be a decisive factor in the determination of the best sequence. Hence, indiscriminate use of several conventional blood group systems in the determination of zygosity of twins from a particular population should be discontinued. The formulae developed in this note are quite general and the procedure explained can easily be generalized to other situations.