To study whether the effects of prognostic factors associated with the occurrence of distant metastases (DM) at primary diagnosis change after the incidence of loco-regional recurrences (LRR) among women treated for invasive stage I or II breast cancer. The study population consisted of 3,601 women, enrolled in EORTC trials 10801, 10854, or 10902 treated for early-stage breast cancer. Data were analysed in a multivariate, multistate model by using multivariate Cox regression models, including a state-dependent covariate. The presence of a LRR in itself is a significant prognostic risk factor (HR: 3.64; 95%-CI: 2.02-6.5) for the occurrence of DM. Main prognostic risk factors for a DM are young age at diagnosis (< or =40: HR: 1.79; 95%-CI: 1.28-2.51), larger tumour size (HR: 1.58; 95%-CI: 1.35-1.84) and node positivity (HR: 2.00; 95%-CI: 1.74-2.30). Adjuvant chemotherapy is protective for a DM (HR: 0.66; 95%-CI: 0.55-0.80). After the occurrence of a LRR the latter protective effect has disappeared (P = 0.009). The presence of LRR in itself is a significant risk factor for DM. For patients who are at risk of developing LRR, effective local control should be the main target of therapy.