The aims were to determine the importance of p53 and bcl-2 expression on the response to chemotherapy with alkylating agents in patients with ovarian cancer. We have followed the response to chemotherapy in a series of 59 patients with ovarian adenocarcinoma designated as p53 and bcl-2 positive or negative by immunocytochemistry. Of these cases, 50 received either cisplatin + treosulfan or treosulfan alone. Immunocytochemistry for p53 was positive in 28/59 tumors. Patients were grouped according to their response to chemotherapy (stable or progressive disease) assessed at 6, 12, and 18 months. There was increasing divergence of p53+ and p53- tumors over time. Of those which were p53+, 25% showed progression at 6 months, 80% at 12 months and 89% progression at 18 months. In contrast, 23%, 50%, and 67% of p53- tumors showed progression at 6, 12 and 18 months respectively. For bcl-2, in 23/55 positive tumors there was progression in 35%, 78% and 94% compared with 25%, 57% and 59% in bcl-2 negative tumors at 6, 12 and 18 months respectively. Those tumors which were bcl-2 and p53 negative were most likely to progress, while those which were bcl-2 and p53 positive had the best prognosis. These differences did not translate into increased overall survival with minimum follow-up of 12 months. This data lends support to our suggestion that despite initially increased susceptibility to alkylating agents, enhanced genomic instability due to p53 inactivation may render tumors more likely to develop resistance to chemotherapy over time. This effect may be altered by bcl-2 function, lack of which will lead to a good response to chemotherapy as the tumor's ability to undergo apoptosis will not be compromised.