AbstractIn some infectious disease studies and 2‐step treatment studies, 2 × 2 table with structural zero could arise in situations where it is theoretically impossible for a particular cell to contain observations or structural void is introduced by design. In this article, we propose a score test of hypotheses pertaining to the marginal and conditional probabilities in a 2 × 2 table with structural zero via the risk/rate difference measure. Score test‐based confidence interval will also be outlined. We evaluate the performance of the score test and the existing likelihood ratio test. Our empirical results evince the similar and satisfactory performance of the two tests (with appropriate adjustments) in terms of coverage probability and expected interval width. Both tests consistently perform well from small‐ to moderate‐sample designs. The score test however has the advantage that it is only undefined in one scenario while the likelihood ratio test can be undefined in many scenarios. We illustrate our method by a real example from a two‐step tuberculosis skin test study.