Binding of G1 cyclins to cyclin-dependent kinases leads to phosphorylation of the retinoblastoma protein and progression through G1 and S phases of the cell cycle. Overexpression of cyclins is thought to deregulate this process and has been noted in many human malignancies. This study was conducted to assess patterns of expression and potential gene amplification of the G1 cyclins in 84 patients affected with extremity soft-tissue sarcomas. Sixty cases were primary tumors, whereas the remaining 24 cases were locally recurrent lesions. There were 58 high-grade and 26 low-grade tumors. Immunohistochemical analyses were conducted using antibodies to cyclins D1, E, and A. Southern blot analysis was performed on DNA available from 53 of 84 patients with a cyclin D1-specific probe. Cyclin D1 overexpression was noted in 23 of 79 informative cases (29%), whereas cyclin E was found overexpressed in 26 of 80 cases (33%) and cyclin A overexpression was observed in 9 of 81 cases (11%). Overexpression of cyclins D1, E, or A each correlated significantly with high tumor grade (P <0.05). On multivariate analysis, neither cyclin E nor cyclin A were significant predictors of outcome. However, overexpression of cyclin D1 was significantly associated with worse overall survival for the entire group as well as in the subset of high-grade lesions (P <0.05), notwithstanding the relatively short follow-up time (mean, 2.4 years). Nevertheless, the presence of a significant association between laboratory data and outcome implies that the study is adequately powered. Furthermore, none of the cases demonstrated CCND1 gene amplification. These data support the concept that cyclin D1 overexpression determines the evolution of a particularly aggressive subset of these lesions.