Age-related decline in thymic T-cell development in 22-month-old C57BL/6J X DBA/2J (BXD) recombinant inbred strains of mice was functionally and phenotypically analyzed and genetically mapped. There was a positive correlation of the concanavalin A (Con A)-induced thymocyte proliferative response with the capability of thymocytes to mature to the CD4+CD8+ stage. The accumulation of CD4-CD8- stage of thymocytes in 22-month-old BXD mice was further identified to be associated with a developmental block between the CD25-CD44+ and the CD25+CD44+ stages. The quantitative trait loci regulating the Con A-induced thymocyte proliferative response were mapped to mouse chromosome 1, 3, and 11, nearest to 32.1 centimorgan (cM), 5.6 cM, and 18.0 cM, respectively. Our results suggest that several genetic loci regulate the intra-thymic T-cell maturation process and play an important role in determining age-related decline in thymic T-cell development. © 2002 Elsevier Science Ireland Ltd. All rights reserved.