BACKGROUND: Little information is available concerning the possible antiproliferative effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on the thyroid gland. We have hypothesized that the antiproliferative effects of statins observed in thyroid cell lines in vitro may have a clinical counterpart that could be detected by investigating the prevalence and size of thyroid nodules in patients on long-term treatment with statins. METHODS: We retrospectively evaluated 135 dyslipidaemic patients receiving statin therapy continuously for at least 5 years, and 137 controls. All the subjects were submitted to ultrasound investigation of the thyroid gland, to establish prevalence, number and volume of thyroid nodules. RESULTS: Subjects treated with statins showed markedly lower prevalence of thyroid nodules (36.3%vs. 67.9%, P < 0.001), as well as reduced number and smaller total volume of lesions, as compared to the control group. A logistic regression analysis, taking into account age, sex, risk factors for the development of thyroid nodules and concomitant drug treatment, revealed that treatment with statins remained the only important predictor of the presence of thyroid nodules [odds ratio (OR) 0.312, 95% confidence interval (CI) 0.156-0.625, P < 0.001] besides risk factors. CONCLUSIONS: Our data provide the first circumstantial evidence of an association between HMG-CoA reductase inhibitor treatment and reduced prevalence, number and volume of thyroid nodules. This finding may be explained by an antiproliferative and/or pro-apoptotic effect of long-term statin treatment on thyroid cells, in vivo.