The EphA2 tyrosine kinase receptor is frequently overexpressed in ovarian cancer and this feature is predictive of poor clinical outcome. Preclinical investigation has also linked EphA2 with p53. In our present study, we examined EphA2 and p53 status (both expression and full-length mutation status) in 6 ovarian cell lines and 79 human ovarian cancers to determine potential associations. EphA2 was overexpressed in 80% of ovarian cancer cell lines and in 75% of clinical specimens. In particular, high levels of EphA2 occurred in 91% of tumors with p53 null mutations compared to 68% in tumors with wild-type or missense mutations (p=0.027). EphA2 expression did not relate to critical versus non-critical site missense p53 mutations or the location of mutations on specific p53 exons. We also demonstrated that while EphA2 and p53 can provide independent information regarding clinical status, the combination of EphA2 and p53 status can predict poor clinical outcome. In particular, the combination of EphA2 overexpression and p53 null status was associated with decreased overall patient survival and related to increased incidence of ascites and distant metastasis. Taken together, these data indicate a complex relationship between EphA2 and p53 that appears to regulate EphA2 expression and clinical outcome.