A homogeneous group of 53 Caucasian subjects with high‐grade osteosarcoma (OS) was typed for HLA‐A and B locus antigens. Although no significant differences in the distribution of these antigens were found in comparison with 425 local controls, a trend towards an increase of HLA‐B18 and decrease of HLA‐B21 was observed. All the patients underwent amputation plus adjuvant chemotherapy and among the 29 patients with a follow‐up longer than one year, 9 out of 10 subjects with HLA‐A3 antigens developed metastases within a few months. None of the OS patients had the HLA‐A3, B7 haplotype which is present in linkage‐disequilibrium in the control population.