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Background: Treatment of chronic hepatitis C with interferon is known to be associated with thyroid dysfunction (TD) in 5–14% of patients. We studied the incidence, types, outcome and risk factors predictive of thyroid dysfunction. Methods: A retrospective analysis was performed on all patients treated with interferon alpha (IFN) or pegylated interferon alpha (PEG-IFN) ± ribavirin (RBV), who developed abnormal thyroid function tests (TFTs). These cases were compared with treatment-matched controls to identify factors predictive of thyroid dysfunction. Statistical methods consisted of: χ2 test, Fischer's exact test, Welch's t-test, and multivariate analysis. Results: From a total of 511 patients, 45 cases with TD were identified (8.8%). Pegylated interferon alpha was associated with higher rates of TD than IFN (14.1% vs 6.0%, P = 0.0029). Female sex (OR 5.6, 95% CI 1.1–7) and Asian ethnicity (OR 2.7, 95% CI 1.4–22) were independent predictors of developing TD. Cytology was obtained in 13 patients: benign follicular pattern (8); thyroiditis (3); and normal (2). Thyroid peroxidase (TPO) antibodies ( P = 0.004) and earlier onset of dysfunction ( P = 0.03) were associated with need for treatment. Sixteen patients had persistent TD by the end of the follow-up period, predicted by female sex, non-Asian ethnicity, prior history of TD and TPO antibodies. Conclusions: Pegylated interferon alpha, female sex and Asian ethnicity are independent risk factors for TD. Thyroid peroxidase antibodies and earlier TD within the course of IFN are associated with the requirement for treatment. Thyroid function tests should be monitored during and after IFN-based therapy. The most common cytological finding is a benign follicular pattern. [ABSTRACT FROM AUTHOR]