One view of hyperemesis gravidarum (HG) is that it is mediated by human chorionic gonadotropin (hCG), which also may lead to elevation of serum thyroid hormone through a process of receptor "cross-talk" with the thyrotropin receptor. Women with HG reportedly have elevated hCG levels, and the same may be the case for those with gestational thyrotoxicosis. There are numerous isoforms of the various components of hCG, and changes in the profile of isoforms conceivably could interact with the absolute serum hCG level to produce HG or gestational thyrotoxicosis. This study examined the relation among hCG isoforms, serum thyroid hormone levels, and HG in European women and also Samoan women, who are known to be at relatively high risk of HG. Ten European and 10 Samoan women with HG were matched for gestational stage with other women who did not have hyperemesis. Serum hCG charge-isoform profiles were recorded by chromatofocusing, and hCG was estimated by a competitive radioimmunoassay that measures intact hCG, nicked hCG, free β-hCG subunit, and β-hCG core fragment. No ethnic differences were found in hCG isoform profiles. Samoan women with HG had the highest serum total hCG levels. Levels in hyperemetic women were significantly higher than in matched control subjects. Women with HG also had increased hCG levels in the more acidic part of the chromatofocusing pH range. Women in all groups had similar serum estradiol levels, but these levels correlated with the hCG concentration in the pH range of 4.01 to 5.2. Hyperemetic women had significantly lower serum thyrotropin levels than control women, and these levels correlated with hCG concentration at pH levels of 2.8 to 4.6. Serum free thyroxine levels correlated with hCG concentration below a pH level of 4.0. After adjusting for hyperemetic versus control status as well as ethnicity, the log-transformed total serum hCG level was the sole significant predictor of serum estradiol and log-transformed serum thyroxine levels. The correlation with estradiol reflected its strong association between log-transformed hCG concentration within the first and second quartiles of the chromatofocusing pH range, encompassing pH values of 4.01 to 5.2. These findings suggest that acidic isoforms of hCG may contribute to both HG and gestational thyrotoxicosis.