Epithelial ovarian cancer still carries a high mortality rate and remains the leading cause of gynecologic cancer death in the USA, despite decades of research. Hence, there is considerable interest in developing biomarkers that could be used to stratify patients for subsequent treatment. Mutation of the p53 tumor suppressor gene occurs very frequently (∼96%) in high-grade serous ovarian cancer. However, loss of p53 has not proven to be a reliable prognostic marker. Recent evidence indicates that the truncated p53 protein isoforms can regulate activated p53 and thus may play a role in tumorigenesis. In the article by Hofstetter et al., the authors examined the relationship between the expression of two p53 isoforms (Δ133p53 and Δ40p53) and prognosis in patients with serous ovarian cancer. Their findings indicate that Δ133p53 constitutes an independent prognostic marker for improved recurrence-free and overall survival. Intriguingly, this relationship was observed in patients whose tumors expressed a mutant p53, suggesting that Δ133p53 might suppress the actions of mutant p53. The mutational status of p53 alone did not have prognostic significance. These studies suggest that mutant p53 activity may be counteracted by Δ133p53, which leads to a more favorable prognosis in advanced serous ovarian carcinomas. Novel therapeutic approaches could be built upon these findings.