Background: Although in vitro breast cancer models have demonstrated a role for protein kinase C ( PKC) alpha and delta isoforms in endocrine insensitivity and resistance respectively, there is currently little clinical evidence to support these observations. Aims: To define the pattern of PKC a and d expression using breast cancer cell lines, with and without endocrine resistance, and also breast cancer samples, where expression can be correlated with clinicopathological and endocrine therapy outcome data. Methods: PKC isoform expression was examined in tamoxifen responsive, oestrogen receptor positive ( ER+), ER+ acquired tamoxifen resistant ( TAM- R) and oestrogen receptor negative ( ER-) cell lines by western blotting and immunocytochemical analysis. PKC isoform expression was then examined by immunohistochemistry in archival breast cancer specimens from primary breast cancer patients with known clinical outcome in relation to endocrine response and survival on therapy. Results: ER+ breast cancer cell lines expressed considerable PKC-delta but barely detectable levels of PKC-alpha, whereas ER- cell lines expressed PKC-alpha but little PKC-delta. ER+ acquired TAM- R cell lines expressed substantial levels of both PKC-alpha and delta. In clinical samples, high PKC- delta expression correlated to endocrine responsiveness whereas PKC-alpha expression correlated to ER negativity. PKC- d was an independent predictor of duration of response to therapy. Patients showing a PKC- delta(+)/ PKC- alpha(-) phenotype had a six times longer endocrine response than patients with the PKC- delta(+)/ PKC-alpha(+) phenotype ( equating to tamoxifen resistance in vitro). Conclusions: Levels of PKC-alpha and delta expression appear to be indicative of response to anti- oestrogen therapy and could be useful in predicting a patient's suitability for endocrine therapy.