Asymptotic tests are commonly used for comparing two binomial proportions when the sample size is sufficiently large. However, there is no consensus on the most powerful test. In this paper, we clarify this issue by comparing the power functions of three popular asymptotic tests: the Pearson’s χ2 test, the likelihood-ratio test and the odds-ratio based test. Considering Taylor decompositions under local alternatives, the comparisons lead to recommendations on which test to use in view of both the experimental design and the nature of the investigated signal. We show that when the design is balanced between the two binomials, the three tests are equivalent in terms of power. However, when the design is unbalanced, differences in power can be substantial and the choice of the most powerful test also depends on the value of the parameters of the two compared binomials. We further investigated situations where the two binomials are not compared directly but through tag binomials. In these cases of indirect association, we show that the differences in power between the three tests are enhanced with decreasing values of the parameters of the tag binomials. Our results are illustrated in the context of genetic epidemiology where the analysis of genome-wide association studies provides insights regarding the low power for detecting rare variants.