Abstract: PENN, D. AND W. K. POTTS. Untrained mice distinguish MHC-determined odors. PHYSIOL BEHAV 64(3) 235-243, 1998.--Immune recognition occurs when foreign antigens are presented to T-lymphocytes by molecules encoded by the highly polymorphic genes of the major histocompatibility complex (MHC). House mice (Mus musculus) prefer to mate with individuals that have dissimilar MHC genes. Numerous studies indicate that mice recognize MHC identity through chemosensory cues; however, it is unclear whether odor is determined by classical, antigen-presenting MHC loci or closely linked genes. Previous studies have relied on training laboratory mice and rats to distinguish MHC-associated odors, but there are several reasons why training experiments may be inappropriate assays for testing if MHC genes affect odor. The aim of this study was to determine whether classical MHC genes affect individual odors and whether wild-derived mice can detect MHC-associated odors without training. In the first experiment, we found that wild-derived mice can be trained in a Y-maze to detect the odors of mice that differ genetically only in the MHC region. In the second and third experiments, we used a naturalistic habituation assay and found that wild-derived mice can, without training, distinguish the odors of mice that differ genetically only at one classical MHC locus (dm2 mutants).