In otherwise euthyroid patients presenting with thyroid enlargement, reduction in serum thyrotrophin (TSH) concentrations measured in a sensitive assay may be a marker of thyroid autonomy and may therefore indicate a benign underlying pathology. We investigated prospectively a cohort of 467 subjects presenting consecutively to our thyroid clinic with nodular or diffuse enlargement of the thyroid. Subjects were divided into those with normal (0.4-5.5 mU/l), low but detectable (0.1-0.39 mU/l) or undetectable (< 0.1 mU/l) serum TSH concentrations. The final pathological diagnosis was defined by fine-needle aspiration cytology and clinical follow-up of at least 2 years or by fine-needle aspiration cytology and histology following surgical treatment. Serum TSH concentrations below normal were found in 75 patients (16.1%), those with low serum TSH results having higher mean free T4 concentrations, were older and were more likely to be female. In those with undetectable serum TSH, no patient had a diagnosis of thyroid neoplasia and in those with low but detectable TSH, thyroid neoplasms were diagnosed in two patients (3.4%). In those with normal serum TSH, 12.0% had a final diagnosis of thyroid neoplasm (p = 0.013). Overall, thyroid malignancy was found in one patient (1.3%) of those with a serum TSH measurement below the normal range and 6.9% of those with normal serum TSH (p < 0.06). Reduction in serum TSH at presentation may identify a group which requires less intensive investigation and follow-up than those without biochemical evidence of thyroid autonomy.