The presence of a placebo arm is certainly a substantial element in randomized control trials (RCTs) because the effectiveness or efficacy of a new therapy can be evaluated through a direct comparison between the test treatment and the placebo arm. Conducting a placebo-controlled RCT is often very difficult or even impossible. To solve this problem, the availability of standard treatments and ethical concerns have led scientists to consider an active or positive control treatment as a comparator to assess the treatment effect without a placebo arm. Such an assessment is often made under a so-called “non-inferiority trial” (NIT) design. Non-inferiority margin (NIM) is the most important part of an NIT. Because there is no well-established method to determine the NIM, it is very important that this margin be pre-specified and the criteria for how it was established well defined prior to conducting the study. All methods of determination of NIM rely upon subjective judgment with unverifiable assumptions. This article demonstrates six simple methods to calculate NIM.