The TRoglitazone In the Prevention Of Diabetes (TRIPOD) trial is a single-center, randomized, placebo-controlled, double-masked study. The primary aim of the TRIPOD trial is to test the hypothesis that chronic administration of troglitazone to nondiabetic women with prior gestational diabetes mellitus (GDM) will improve whole-body insulin sensitivity and reduce the incidence of non-insulin-dependent diabetes (NIDDM). Because troglitazone is already known to lower blood glucose concentrations in persons who have developed NIDDM, an additional aim of the project will be to determine whether early intervention with troglitazone will achieve better final glycemic control than can be achieved by later intervention. In addition, since troglitazone treatment is expected to improve insulin sensitivity and may prevent or delay a decline in glucose tolerance, we also plan to determine whether long-term troglitazone treatment alters the development or progression of atherosclerosis. In this article we describe the experiment's design, the study's endpoints and methods for determining those endpoints, methods for assessing quality of life, and proposed methods for statistical analyses. The unique two-phase study design of the TRIPOD trial will permit testing not only of the biological question about reversal of insulin resistance and prevention of diabetes, but also of the clinical question about whether early intervention is superior to late intervention. Results from this trial will have an important impact on the monitoring and treatment of patients at high risk for NIDDM.