D-dopachrome tautomerase (D-DT/MIF-2) is a member of the macrophage migration inhibitory factor (MIF) cytokine superfamily, and a close structural homolog of MIF. MIF and D-DT have been reported to be involved in obesity, but there is little known about the regulation of D-DT in adipose tissue inflammation and wound healing. Subcutaneous adipose tissue was collected from 54 healthy donors and 28 donors with acutely inflamed wounds undergoing wound debridement. In addition, epididymal fat pads of mice were injected with lipopolysaccharide to study receptor expression and cell migration in vivo. D-DT protein levels and mRNA expression were significantly decreased in subcutaneous adipose tissue adjacent to acutely inflamed wounds. D-DT improved fibroblast viability and increased proliferation in vitro. While D-DT alone did not have a significant effect on in vitro fibroblast wound healing, simultaneous addition of neutralizing MIF antibody resulted in a significant improvement of fibroblast wound healing. Interestingly, expression of the MIF and D-DT receptor CD74 was down-regulated while the MIF receptors CXCR2 and CXCR4 were up-regulated primarily on macrophages indicating that the MIF-CXCR2/4 axis may promote recruitment of inflammatory cells into adipose tissue. Our results describe a reciprocal role of D-DT to MIF in inflamed adipose tissue, and indicate that D-DT may be beneficial in wound repair by improving fibroblast survival and proliferation.