Turkey osteomyelitis complex (TOC) is defined by the US Food Safety Inspection Service (FSIS) to include normal-appearing processed turkey carcasses that contain lesions including green discoloration of the liver, arthritis/synovitis, soft-tissue abscesses, and osteomyelitis of the proximal tibia. The lesions are associated with many different opportunistic organisms, mainly Staphylococcus aureus and Escherichia coli, suggesting that TOC incidence may be influenced more by deficiencies in the host immune response rather than by the virulence of any one organism. This syndrome is primarily a disease of adolescent male turkeys, and birds with TOC lesions have decreased indices of cell-mediated immunity, leading to the hypothesis that defects in the immune response of individuals within flocks of male turkeys may be responsible for the occurrence of these opportunistic infections. We have developed an experimental model for this disease in which treatment with dexamethasone (DEX), either with or without air sac inoculation with Escherichia coli, produces all of the lesions associated with TOC. These studies suggest that TOC is a result of stress-induced immunosuppression in a subpopulation of male turkeys that respond to the stressors in modern poultry production in a detrimental manner. Supplemental vitamin D3 treatment protected male turkeys from the immunosuppression induced by multiple treatments with DEX and resulted in decreased incidence of mortality, TOC, green liver, and isolation of bacteria from tissues, lower air sacculitis scores, and lower heterophil to lymphocyte ratios than nonsupplemented controls. Vitamin D3 also protected BW; relative weights of the liver, heart, spleen, and bursa; and clinical chemistry values from the effects of DEX treatment. The ability of vitamin D3 supplementation to protect turkeys from the immunosuppressive effects of severe stress emphasizes its role as a prohormone that affects health and disease resistance in turkeys and suggests that variation in the vitamin D receptor genotype may be involved in this disease process. This model has potential value in the identification of other nutritional and physiological immunomodulators that can decrease TOC incidence and will provide a means for the divergent selection of birds more resistant to the stressors of turkey production. In addition, this model will provide justification for management options designed to minimize stress.