We have determined the frequency of specific mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas (MTCs) and correlated the presence or absence of a codon 918 mutation with the clinical characteristics of these tumours. Thirty paraffin-embedded sporadic MTCs and two frozen MTCs were collected for analysis of specific mutations in the RET proto-oncogene in codons 609, 611, 618 and 620 (exon 10); 630 and 634 (exon 11); 768 (exon 13); 883 (exon 15) and 918 (exon 16). A novel primer was designed which introduced a restriction site for Rsal in the presence of the specific codon 918 mutation (ATG-->ACG) in these tumour samples. A 'clinical-genetic' correlation was performed comparing the presence of absence of the codon 918 mutation with the following clinical characteristics: age at diagnosis, tumour size, presence or absence of metastases, MTC related morbidity, and base line calcitonin levels at diagnosis or most recent follow-up. Patients were classified as having sporadic MTC if there was no family history of C-cell hyperplasia, MTC, phaeochromocytoma or parathyroid disease. Retrospective review of patient records enabled complete clinical data to be obtained in 28 of 32 patients. Base line calcitonin levels were measured by radioimmunoassay or calcitonin enzyme linked immunoassay. Cysteine codons in exons 10 and 11, specifically codons 609, 611, 618, 620, 630 and 634, were screened for the presence of mutations by sequence analysis. Specific mutations occurring at codons 768, 883 and 918 were screened for by restriction endonuclease digestion of PCR products. The mutation at codon 918ATG-->ACG was found in 21 of 32 (66%) MTCs and the mutation at codon 883GCT-->TTT was found in one of 32 MTCs. Where possible, the presence of 'germline-type' mutations in codons 609, 611, 618, 620, 630 and 634 were excluded. Ten MTCs did not have a mutation in codons 768, 883 or 918 of the RET proto-oncogene. The presence or absence of the somatic mutation at codon 918 did not correlate with any of the above clinical characteristics. Somatic mutations in the RET protooncogene occur frequently in sporadic MTCs.