Mutations of the p53 gene are relatively rare in synovial sarcoma. With this in mind we investigated the potential of the HDM2 antagonist, nutlin-3 to induce p53 activity in synovial sarcoma cells lines. Nutlin-3 effectively promoted p53 stability which was concurrent with the activation of p53 target genes, growth arrest and apoptosis. Analysis of synovial sarcoma cells showed that p53 is effectively stabilized in response to DNA damage; however transcriptional activation of p53 target genes p21 and HDM2 is abrogated. Co-immunoprecipitation studies showed the presence of high levels of p53-HDM2 complexes in doxorubicin but not nutlin-3 treated cells suggesting that HDM2 association is responsible for the loss of p53 activity. Our results support the hypothesis that p53 function is suppressed by aberrant HDM2 activity and suggest the possibility of targeting the p53-HDM2 regulatory axis as a therapeutic strategy in synovial sarcoma.