Clinical trials testing the safety and efficacy of immunosuppressive agents for the treatment of autoimmune diseases should also be designed to evaluate immunocompetency. The most clinically relevant outcome for assessing immunocompetency is the infection rate. Therefore, a systematic approach to screening, monitoring, and reporting infections, modeled after the recommendations of the American Society of Transplantation, is presented. However, because the baseline infection rate in most autoimmune diseases is low, additional tests for immunocompetency should be considered. Evaluation of vaccine responses, an alternative clinically relevant approach, may be particularly useful. Other adjunctive approaches to evaluation of immunocompetency are discussed including immunization with non-vaccine neoantigens, surveillance of chronic viral infections, in vivo or in vitro assessment of cellular immunity, and analysis of innate immunity. Banking genetic material to allow genotyping should be considered particularly if a central repository for samples from different trials can be established.