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Studies have shown that radioactive iodine therapy (RAIT) affects the development of second cancer in thyroid cancer patients. The impact of other factors, such as dyslipidemia are not clear. A retrospective analysis of thyroid cancer patients with a 1,251,913 person-year follow-up was conducted using data from the Health Insurance Review and Assessment database in South Korea from January 2008 to December 2018. We investigated factors related to second cancer development using a nested case-control analysis to avoid length bias. The overall risk of developing second cancer was higher in thyroid cancer patients than in the general population [standardized incidence ratio, 3.34; 95% confidence interval (CI) 3.30–3.39]. Second cancer incidence was higher in patients who received RAIT than in those who did not [odds ratio (OR) 1.130; 95% CI 1.094–1.169]. Moreover, the risk of second cancer was higher in patients with dyslipidemia than in those without dyslipidemia (OR 1.265; 95% CI 1.223–1.309). After adjustment for RAIT, the incidence of a second cancer was higher in patients with dyslipidemia than in those without dyslipidemia (OR 1.262; 95% CI 1.221–1.306). The risk of second cancer development in patients with thyroid cancer appears to be high. Dyslipidemia may be associated with an increased risk of several types of second cancers.