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Killer cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIRgene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIRgenes and their cognate HLAligands on childhood ALL risk. Genotyping of 16 KIRgenes, along with HLAclass I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIRgenes, KIRhaplotypes, and combinations of KIR-HLAligands were tested for disease association using logistic regression analyses. KIRA/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIRgenotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIRgenes and their HLAligands in childhood ALL etiology that may vary among ethnic groups.