Background: There is increasing evidence that patients (pts) with wild type p53 have higher response rates to single agent carboplatin and may gain no benefit from the addition of paclitaxel chemotherapy. We tested two hypotheses in the context of a controlled clinical trial: 1) Tumours with wild-type p53 are more sensitive to platinum based chemotherapy than those with mutant p53, so will survive longer; 2) Pts whose tumours have mutant p53 benefit from the addition of paclitaxel to treatment, whilst those with wild type p53 do not. Methods: We collected 265 archival diagnostic tissue samples from pts that took part in the UK Medical Research Council ICON3 ovarian cancer trial comparing carboplatin or CAP (cyclophosphamide, doxorubicin, cisplatin) vs carboplatin plus paclitaxel. We examined the tissue for p53 mutations by genomic DNA sequencing of the coding exons and adjacent splice sites. Overall survival (OS) was updated for this study. A Cox regression model was applied in the analysis. Results: Mutations of p53 were detected in 130/265 (49.1%) pts tumour samples. With a median follow up of 12 years, a total of 214 (84%) pts had died. In univariate analysis, the presence of p53 mutations was associated with worse OS for pts who received single agent carboplatin [HR (95%CI)=1.72(1.14-2.60), p=0.0099, n=121] and p53 status retained independent prognostic significance after adjusting for age, stage, residual bulk, grade and histology [HR (95% CI)=1.89 (1.20-2.93), p=0.0059]. For the second hypothesis (n=265), pts whose tumours had mutant p53 showed greater benefit from the addition of paclitaxel to their treatment [HR (95%CI)=0.64(0.43-0.95) p=0.027] compared to patients with wild-type p53 tumours [HR (95%CI)=1.02(0.68-1.54) p=0.92]. Conclusions: We conclude that p53 is an independent prognostic biomarker for OS in ovarian cancer, particularly for patients receiving single agent carboplatin. Furthermore, the addition of paclitaxel shows OS benefit for pts with p53 mutant tumours, but not for those with wild-type p53 tumours.