The aryl hydrocarbon receptor (AHR) is a cytosolic transcription factor with numerous endogenous and xenobiotic ligands, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recent data suggest that TCDD may induce regulatory T cells, while a second AHR ligand, FICZ, promotes Th17 differentiation. The aim was to examine whether the injection of recipient mice with either TCDD or FICZ altered skin allograft rejection in a fully mismatched model. TCDD or FICZ was given to recipient C57BL/6 mice intraperitoneally (IP). Twenty-four hours later, donor skin was grafted from BALB/c mice. An additional dose of FICZ was given on day 3. Treatment with TCDD delayed graft rejection for more than 4 weeks while FICZ treatment accelerated the rejection by 1–2 days. In vivo exposure with TCDD led to a rise in the frequency of FoxP3⁺ CD4⁺ T cells in the spleen, while FICZ increased IL-17 secretion by splenocytes from the treated animals. Activation of the AHR receptor by different AHR ligands in vivo resulted in opposing the effects on skin graft survival. AHR serves as a sensor to environmental signals, with effects on the acquired immune system that may alter outcomes after organ transplantation. This model will be useful to further delineate direct effects of the environment on the immune system and outcomes of organ transplantation.