Objective To explore the changes and clinical significance of serum levels of homocysteine and c-reactive protein in diabetic patients with sub-clinical hypothyroidism. Methods The serum levels of homocysteine and c-reactive protein in 60 cases of diabetic patients with sub-clinical hypothyroidism and 120 cases of diabetic patients with normal thyroid function were measured and the difference were analyzed. Results The serum levels of homocysteine and c-reactive protein in diabetic patients with sub-clinical hypothyroidism were significantly higher than that of diabetic patients with normal thyroid function (P < 0.05). Conclusion The serum levels of homocysteine and C-reactive protein can be used as index to predict the risk of atherosclerosis and cardiovascular disease in diabetic patients with sub-clinical hypothyroidism.