We have shown that TP53 protein accumulation predicts a poor response to hormonal therapy in recurrent breast cancer. To evaluate whether TP53 protein accumulation can predict the response to chemotherapy in patients with recurrent breast cancer, TP53 protein levels were measured in routinely prepared cytosols from primary breast tumors, using a quantitative luminometric immunoassay (Sangtec Medical). Patients who developed recurrent disease received either first-line chemotherapy (n = 92; 48% premenopausal, 30% ER/PgR-positive, 60% with a disease-free interval [DFI] > 12 months), or first-line hormonal therapy followed by chemotherapy (n = 180; 27% premenopausal, 67% ER/PgR-positive, 67% with a DFI > 12 months). In univariate analysis, TP53 protein accumulation does not predict response to first-line chemotherapy. With respect to chemotherapy after tamoxifen therapy, TP53 protein accumulation only showed a relation with progression free-survival when analyzed as a dichotomized (cut-off value 1.6 ng/mg protein) variable (p = 0.02), but not as a continuous variable, with a relative hazard rate (95% confidence limits) of 1.5 (1.1-2.2). In conclusion: patients with high TP53 protein levels, as measured by LIA, respond poorly to chemotherapy only after failure to tamoxifen therapy.