The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance.