It has been established that soy products can interfere with thyroid hormone absorption resulting in continued hypothyroidism in individuals receiving recommended levothyroxine replacement. It has also been reported that achievement of euthyroidism in hypothyroid patients using soy products requires increased doses of levothyroxine. We have observed 2 patients with congenital hypothyroidism who continued to manifest clinical hypothyroidism while receiving recommended doses of hormone and ingesting soy products. The first patient was diagnosed by newborn screening (thyroid-stimulating hormone [TSH] =169 µIU/mL) and treated with 50 µg of levothyroxine since 6 days of age while simultaneously starting soy formula. At 3 weeks of age, she was clinically and biochemically hypothyroid (thyroxine = 4.0 µg/dL, TSH = 216 µIU/mL). We stopped her soy formula and decreased her levothyroxine dose. Three weeks later signs of hypothyroidism were resolving, and, by 10 weeks of age, she was clinically and biochemically euthyroid. Another patient was diagnosed by newborn screening, received levothyroxine, and did well. She was lost to us for 2 years. During this interval she began consuming soy milk and became profoundly hypothyroid (free thyroxine <0.4 ng/dL, TSH = 248 µIU/mL), even though the primary care physician had increased her levothyroxine dose to 112 µg/day. She was switched to cow milk, and her thyroid function slowly normalized with decreasing doses of levothyroxine. These 2 patients reinforce the importance of remembering that soy products interfere with levothyroxine absorption and can endanger infants and young children with congenital hypothyroidism who are at risk for developmental and growth delay.