Infants in developing countries are at risk of concurrent micronutrient deficiencies, because the same causative factors may lead to deficiencies of different micronutrients. Inadequate dietary intake is considered one of the major causes of micronutrient deficiencies, especially among poor and underprivileged children in developing countries. Operational strategies and distribution systems are often duplicated when supplementation programs for single micronutrients are implemented at the same time. The International Research on Infant Supplementation (IRIS) trial was conducted in four distinct populations on three continents: Africa, Latin America, and Asia. The participating countries were South Africa, Peru, Vietnam, and Indonesia. The study had a randomized, doubleblind, placebo-controlled design. Each country aimed to enroll at least 70 infants per intervention group (65 + 5 anticipated dropouts). The micronutrient vehicle was in the form of a "foodlet" (food-like tablet) manufactured as chewable tablets, which were easy to break and dissolve, and which had the same taste, color, and flavor for all countries. Children were randomly assigned to one of four 6-month intervention groups: group 1 received a daily foodlet containing multiple micronutrients; group 2 received a daily placebo foodlet containing no micronutrients; group 3 received a weekly foodlet that contained multiple micronutrients (twice the dose of the daily foodlet) and placebo foodlets on the other days of the week; group 4 received a daily foodlet containing only 10 mg of elemental iron. The IRIS Trial aimed to examine the prevalence of multi-micronutrient deficiencies in 6- to 12-month-old infants from rural populations, and to examine the efficacy of multi-micronutrient supplementation in infants from the different countries included in the study. This paper describes the general methodology of the IRIS trial and the operational differences among the country sites.