Omphalocele is a congenital midline defect into the base of the umbilical cord, which frequently contains herniated abdominal viscera. Giant omphaloceles (GOs) are defined as larger than 5 cm. Management of omphaloceles is usually focused on closing the abdominal wall defect after supportive care to stabilize the patient. Some clinicians prefer a nonoperative “paint and wait” strategy without graft closure; the sac is maintained with topical medications such as silver sulfadiazine or combinations of polyvinylpyrrolidone and iodine (the most frequently used commercial preparation being povidone-iodine®) mixed with topical antibiotic powder sprays. Povidone-iodine can cause thyroid dysfunction, especially in preterm infants. The authors present one such case in the article; the goal is to sensitize the medical care-providers to these adverse effects. A female infant born at 26⁺² weeks’ gestation/birth weight of 830 gm showed a GO with intact membranes. A transparent silicone adhesion wound-contact dressing was used to cover the abdominal herniation, and on the 2nd postnatal day, the surgeon began applying povidone-iodine over the omphalocele followed by nonadherent dressings. Serum thyroid stimulating hormone (TSH), free T4, and iodine levels were followed over time. The iodine levels were monitored but the levels at 35 weeks’ corrected gestational age suddenly rose to 33,917 μg/L (normal 40−100 µg/L). The infant was still receiving daily povidone-iodine dressings at this time. These dressings were stopped immediately, and the serum iodine levels dropped to 97 μg/L in 2 months. The authors seek to remind that infants, especially preterm, who are exposed to repeated topical exposure to iodine-containing antiseptic solutions over a large surface area are at risk of developing transient hypothyroidism. There is a need to remain cognizant of these complications and be aware of the need for close monitoring of thyroid function in high-risk infants.