Postpartum thyroid dysfunction (PPTD) occurs in 5% of women, with hypothyroidism developing in 23% of these after 3-5 yr. We have determined the prognostic significance of thyroid peroxidase antibody (TPOAb), thyroid ultrasound morphology (U/S), human leukocyte antigen haplotype, and postpartum thyroid status on the development of thyroid dysfunction 77-81 months after PPTD. Ninety-eight TPOAb-positive [48 who had developed PPTD (group 1) and 50 without PPTD (group 2)] and 70 TPOAb-negative (group 3) women (derived from 145 TPOAb-positive and 229 TPOAb-negative cohorts at the index pregnancy), with comparable ages, parity, pregnancies after index pregnancy, and follow-up duration, were studied. Thyroid dysfunction occurred in 46% of group 1 vs. 4% of group 2 (P<0.001) and 24.5% of groups 1 and 2 vs. 1.4% of group 3 (P<0.001). Factors predictive of thyroid dysfunction included a hypothyroid form of PPTD, TSH more than 20 mU/L, and higher TPOAb levels (213.8 kIU/L in group 1 vs. 131.8 kIU/L in group 2; P<0.002) during the postpartum period. Although TPOAb was higher in group 1 than in group 2 at follow-up (166 vs. 97.7 kIU/L; P<0.03), there was no significant fall in TPOAb levels within either group during the period of follow-up. The prevalence of ultrasound hypoechogenicity was higher in group 1 than in group 2 at follow-up (76% vs. 52%; P<0.006), but U/S improved in 62.5% of group 1 during the period of follow-up. Human leukocyte antigen DR10 was lower in those who developed late thyroid dysfunction. These data, representing the longest follow-up of PPTD women, clearly show that the hypothyroid form of PPTD, high TPOAb levels, and a hypoechogenic U/S pattern lead to a high risk (relative risk, 32) of long term thyroid dysfunction. This compares with a relative risk of 12.9 for TPOAb- and PPTD-positive women, who remained euthyroid at the end of the first postpartum year, and 2.8 for TPOAb-positive but PPTD-negative women, all compared to TPOAb-negative women. Therefore, long term surveillance of TPOAb- and PPTD-positive women (group 1) is indicated.