Our objective was to determine whether oral etoposide and cisplatin combination (EoP) is superior to paclitaxel in the treatment of advanced breast cancer (ABC) patients pretreated with anthracyclines. From December 1997 to August 2003, 201 patients were randomised, 100 to EoP and 101 to paclitaxel arms. Four patients in each arm were ineligible. The doses of etoposide and cisplatin were 50 mg p.o. twice a day for 7 days and 70 mg m-2 intravenously (i.v.) on day 1, respectively, and it was 175 mg m-2 on day 1 for paclitaxel. Both treatments were repeated every 3 weeks. A median of four cycles of study treatment was given in both arms. The response rate obtained In the EoP arm was significantly higher (36.3 vs 22.2%; P = 0.038). Median response duration was longer for the EoP arm (7 vs 4 months) (P = 0.132). Also, time to progression was significantly in favour of the EoP arm (5.5 vs 3.9 months; P = 0.003). Median overall survival was again significantly longer in the EoP arm (14 vs 9.5 months; P = 0.039). Toxicity profile of both groups was similar. Two patients in each arm were lost due to febrile neutropenia. The observed activity and acceptable toxicity of EoP endorses the employment of this combination in the treatment of ABC following anthracyclines. © 2005 Cancer Research UK.