The primary objective was to describe the prevalence and characteristics of microbiologically defined infections and infection-related mortality (IRM) in 492 children with acute myeloid leukemia enrolled on CCG 2961. Secondary objectives were to determine the relationship between demographic, disease-related, and therapeutic variables, and infections and IRM. Institutions documented infections prospectively. Age, ethnicity, body mass index, leukemia karyotype, treatment, and institutional size were examined for association with infection outcomes. More than 60% of children experienced such infections in each of 3 phases of chemotherapy. There were 58 infectious deaths; cumulative incidence of IRM was 11% plus or minus 2%. Thirty-one percent of infectious deaths were associated with Aspergillus, 25.9% with Candida, and 15.5% with alpha hemolytic streptococci. Age older than 16 years (hazard ratio [HR], 3.32; 95% confidence interval [CI], 1.87-5.89; P < .001), nonwhite ethnicity (HR, 1.85; 95% CI, 1.10-3.09; P = .02), and underweight status (HR, 3.06; 95% CI, 1.51-6.22; P = .002) were associated with IRM, while size of the treating institution was not. Thus, age, ethnicity, and BMI were important contributors to IRM. Fungi and Gram-positive cocci were the most common organisms associated with IRM and, in particular, Aspergillus species was the largest contributor to infectious deaths.