Little is known about factors contributing to disease-evolution in early-phase myelodysplastic syndromes (MDS). In this article, low erythropoietin (EPO) production is discussed as a 'non-oncogenic' co-factor responsible for disease-manifestation in a group of patients with low-risk MDS. The hypothesis is based on the observations that (i) individuals with bone marrow dysplasia and MDS-related karyotypes but relatively high EPO levels may present without anemia and thus without frank MDS over years, (ii) several elderly patients with idiopathic anemia are low EPO producers and their anemia can be corrected with EPO therapy, and (iii) the well-known fact that low-risk MDS patients typically respond to EPO therapy when they have low endogenous EPO levels.