OBJECTIVE: This study aimed to analyze the autonomic control of heart rate variability (HRV) in subjects receiving chronic l-thyroxine (l-T4) treatment after total thyroidectomy and (131)I therapy for differentiated thyroid carcinoma. METHODS: Blood pressure (BP) and sympatho-vagal activity (evaluated by power spectral analysis (PSA) of time-domain parameters of HRV) were studied in clinostatism and after orthostatism in 24 healthy controls, and in 12 patients taking l-T4 (125-200 mug/day) to maintain serum TSH levels at <0.01 muIU/ml. The study of HRV by PSA is a non-invasive method of analyzing sympatho-vagal control of HRV by quantifying high-frequency (HF) (0.15-0.4 Hz) and low-frequency (LF) (0.04-0.15 Hz) powers. RESULTS: Patients on L-T4 treatment had undetectable TSH levels, serum free T4 (fT4) above the normal range or at the upper limit in one case, and normal free tri-iodothyronine (fT3) levels. Heart rate and R-R intervals were not different in the two groups, both in clinostatism and in ortostatism. Systolic and mean BP were higher in patients than in controls and were inversely correlated with actual serum fT4 levels. During clinostatism, thyroid patients showed significantly lower LF power (P = 0.035), LF/(LF + HF) (P = 0.008) and LF/HF (P = 0.01) than controls. When patients moved from lying to standing, there was a significantly different decrease in orthostatic LF power (P = 0.001), LF/(LF + HF) (P = 0.044) and LF/HF (P = 0.047) versus controls. CONCLUSIONS: Changes in autonomic control of HRV, characterized by decreased sympathetic activity and impaired sympatho-vagal balance with preserved vagal tone, are detectable in patients with hyperthyroxinemia due to suppressive l-T4 therapy and increased systolic and mean, but not diastolic, BP.