Exposure to perfluorooctane sulfonic acid (PFOS) is known to induce thyroid-related adverse effects in aquatic organisms. Because an antioxidant defense mechanism is one of the key functions of the thyroid gland, we examined whether preexposure to PFOS could disrupt thyroid function and enhance cadmium (Cd)-induced oxidative stress in fish. Zebrafish embryos were exposed to control or 0.5 mg/L PFOS for 7 d after fertilization and subsequently exposed to 0.038 mg/L of Cd2t or a mixture of the PFOS and Cd for an additional 3 d until 10 d postfertilization (dpf). Survival rates, body length, messenger RNA (mRNA) expressions related to thyroid function and oxidative stress, the levels of thyroid hormones, and malondialdehyde and antioxidant enzyme activities were measured. Significant down-regulation of mRNAs related to thyroid function (thyroid hormone receptor-alpha [THRa], thyroid hormone receptorbeta [THRb], hematopoietically expressed homeobox [hhex], and paired box gene 8 [pax8]) and decrease of throxine (T4) levels were observed in the PFOS preexposure group, suggesting that PFOS preexposure would influence the performance of thyroid gland in the later stages of life. Certain genes relative to oxidative stress, such as superoxide dismutase 1 (sod1) and heat shock protein 70 (hsp70), in the PFOS preexposure group were significantly up-regulated when the larvae were subsequently exposed to Cd or to the mixture of PFOS and Cd. Glutathione S-transferase activity and malondialdehyde levels of the PFOS-preexposed group were increased significantly by Cd exposure. Significant decrease of the survival rates and body length of fish were observed at 10 dpf among the larvae that were previously exposed to PFOS. These results suggest that preexposure to PFOS could affect antioxidant defense mechanisms and potentially increase the toxicity of Cd on mRNA expression and enzyme activity level responses, as well as on survival or growth of individuals.