As one aspect of the complex feature of longevity, gene by sex interaction plays an important role in influencing human life span. With advances in molecular genetics, more studies aimed at assessing gene by sex interaction are expected. New and valid statistical methods are needed. In this article, we introduce a nontraditional approach, the case-only design, which was originally proposed for assessing gene and disease associations, to detect gene by sex interaction in human longevity. Applications of this method to data collected from centenarian studies show that it can produce consistent results as compared with results obtained from case-control and other approaches. The method cannot be used as a substitute for traditional case-control studies since it is limited to the detection of interactions only. However, the easily applicable case-only approach can be an important tool for screening many potential genes that contribute to human longevity.