Extracellular signal-regulated kinase (ERK)1/2 signalling mediates communication between growth factor receptors and the cell nucleus and has been linked to several key events in the transformation process such as proliferation and invasion. We therefore sought to delineate the degree of phosphorylated ERK1/2 in breast cancer and potential links to upstream receptors such as VEGFR2, ErbB2, downstream targets, such as Ets-2, as well as clinico-pathological parameters, clinical outcome and response to tamoxifen. ERK1/2 phosphorylation was assessed by immunohistochemistry using a phospho-specific ERK1/2 antibody in three breast cancer cohorts including a total of 886 tumours arranged in tissue arrays. Cohort I consisted of 114 patients, cohort II of 248 postmenopausal patients randomized to either 2 years of tamoxifen or no adjuvant treatment and cohort III of 524 patients. Surprisingly, ERK1/2 phosphorylation correlated inversely with tumour size. Phosphorylated ERK1/2 was further associated with the presence of VEGFR2 (cohorts II and III) and the degree of phosphorylated Ets-2, indicating in vivo, a signalling cascade from VEGFR2 via ERK1/2 to Ets-2 phosphorylation. Interestingly, ERK1/2 phosphorylation correlated with better survival in untreated patients independently of lymph-node status and tumour size indicating that ERK1/2 signalling might be associated with a less aggressive phenotype. Finally, patients with oestrogen receptor positive and ERK1/2 phosphorylated tumours also had an impaired tamoxifen response.