MYMD-1 is a synthetic derivative of tobacco alkaloids, compounds that possess immunoregulatory properties and have been linked to the epidemiological observation that smoking reduces the odds of developing thyroid Abs and hypothyroidism. To assess the effect and mechanism(s) of the action of MYMD-1, we chose the NOD.H-2h4 mouse model of spontaneous thyroiditis. We began in vitro using T cells isolated from NOD.H-2h4 spleens and found that MYMD-1 suppressed TNF-α production by CD4+ T cells in a dose-dependent manner. We then treated 58 NOD.H-2h4 mice for 12 wk with either unsupplemented water that contained (10 mice) or did not contain (16 mice) MYMD-1 (185 mg/l) or water supplemented with sodium iodide (500 mg/l) that contained (16 mice) or did not contain (16 mice) MYMD-1. Mice were bled at baseline and then every 2 wk until sacrifice. MYMD-1 decreased the incidence and severity (p< 0.001) of thyroiditis, as assessed by histopathology. Similarly, the number of CD3+ T cells and CD19+ B cells infiltrating the thyroid was dampened by MYMD-1, as assessed by flow cytometry. Interestingly, the subset of thyroidal CD3+CD4+Tbet+RORγT−effector Th1 cells and the systemic levels of TNF-α were decreased by MYMD-1. Serum thyroglobulin Abs decreased in the MYMD-1 group. Thyroid hormones did not differ among the four groups, whereas thyroid-stimulating hormone increased upon iodine supplementation but remained normal in MYMD-1–treated mice. Overall, the study suggests that MYMD-1 ameliorates thyroiditis acting on specific lymphoid subsets. Further studies, including other models of autoimmunity, will confirm the potential clinical use of MYMD-1 as a novel immunometabolic regulator.