The polymorphism of the major histocompatibility complex class I chain-related A gene is associated with type 1 diabetes mellitus. The major histocompatibility complex class I chain-related A gene 5 allele is significantly more frequent in Caucasian type 1 diabetes mellitus children than in healthy subjects, but no information is available on the association with adult-onset type 1 diabetes mellitus or with the so-called slowly progressive latent autoimmune diabetes of the adult in the same ethnic group. In this study we estimated the frequency of major histocompatibility complex class I chain- related A gene alleles and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and human leukocyte antigen-DRB1*04- DQA1*0301-DQB1*0302 in 195 type 1 diabetes mellitus subjects, in 80 latent autoimmune diabetes of the adult subjects, and in 158 healthy subjects from central Italy. Major histocompatibility complex class I chain-related A gene 5 was significantly associated with type 1 diabetes mellitus only in the 1-25 yr age group at diagnosis, and the odds ratio of the simultaneous presence of both major histocompatibility complex class I chain-related A gene 5 and human leukocyte antigen-DRB1*03- DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 was as high as 54 and higher than 388 when compared with double negative individuals. Adult-onset type 1 diabetes mellitus (age at diagnosis, >25 yr) and latent autoimmune diabetes of the adult were significantly associated with major histocompatibility complex class I chain-related A gene 5.1, which was not significantly increased among diabetic children. Only the combination of major histocompatibility complex class I chain-related A gene 5.1 and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 conferred increased risk for adult-onset type 1 diabetes mellitus or for latent autoimmune diabetes of the adult. Our study provides demonstration of the existence of distinct genetic markers for childhood/young-onset type 1 diabetes mellitus and for adult-onset type 1 diabetes mellitus/latent autoimmune diabetes of the adult, namely major histocompatibility complex class I chain-related A gene 5 and major histocompatibility complex class I chain-related A gene 5.1, respectively.