Mutation of the K-ras oncogene occurs frequently in human malignancy. However, there are few reports concerning K-ras mutations in soft-tissue sarcoma, including leiomyosarcoma. We therefore designed a study to determine the prevalence of mutations in the first exon of K-ras in leiomyosarcoma and to evaluate its prognostic potential. Fifty-one leiomyosarcomas were reviewed, and their diagnoses were confirmed on pathological review. Tissue blocks were retrieved, and new sections were prepared for confirmation of diagnosis. Additional tissue sections were used for DNA isolation. PCR and denaturing gradient gel electrophoresis (DGGE) were used to detect K-ras mutations in the first exon of genomic DNA isolated from the specimens. Seven (14%) K-ras mutations were detected using DGGE. Subsequent sequencing of the K-ras gene from each of the mutated tumors confirmed the DGGE results in each case. The median survival for patients whose tumors did not contain mutations of K-ras was 42 months (n = 42) versus 25 months (n = 7) for those with mutations (P = 0.06). However, patients with stages I and II tumors had a median survival of 82 months (n = 28) compared to 28 months for those with stages III and IV disease (n = 20, P = 0.02). The results suggest that K-ras codon 12 mutations are uncommon in leiomyosarcoma; however, when such mutations are found, there is a trend toward worse survival. Furthermore, the data confirm that stage is a significant prognostic indicator.