Haemopoietic growth factors (HGF), i.e. erythropoietin [recombinant human erythropoietin (rHEPO)] or granulocyte colony stimulating factor (G-CSF), alone or in combination, have largely been used to treat anemia in myelodysplastic syndromes (MDS), but whether combined rHEPO and G-CSF is really superior to rHEPO alone is still under debate. In particular, randomized studies comparing front-line rHEPO vs rHEPO+G-CSF are still lacking. The aim of this study was to compare the effects of “standard” doses of rHEPO with the combination of rHEPO and G-CSF in the treatment of anemic patients with low-risk MDS in a prospective randomized trial. Anemic patients with low-risk MDS were randomly assigned to receive either rHEPO (10,000 IU s.c. three times a week) or the same dosage of rHEPO+G-CSF (300 μg s.c. twice a week) for a minimum of 8 weeks. Patients who were unresponsive to rHEPO were offered the combination therapy for another 8 weeks, whereas non-responders to rHEPO+G-CSF were considered “off study”. Responders continued the treatment indefinitely. Both haematological response and changes in quality-of-life (QoL) scores (Functional Assessment of Cancer Therapy-Anemia) were recorded and evaluated. Thirty consecutive patients [10 refractory anemia (RA), 5 RA with ringed sideroblasts, 7 refractory cytopenia with multilineage dysplasia, 5 RA with less than 10% blasts and 3 5q-syndrome] were enrolled in the study. All of them (15 in the rHEPO arm and 15 in the rHEPO+G-CSF arm) were valuable after the first 8 weeks of treatment. Erythroid response was observed in 6/15 (40%) patients in the rHEPO arm and in 11/15 (73.3%) patients in the rHEPO+G-CSF arm. In 4/9 (44.4%) patients who were unresponsive to rHEPO, the addition of G-CSF induced erythroid response at 16 weeks. No relevant adverse effects were recorded for either treatment in any of the study patients. Erythroid response to HGF was associated with a relevant improvement in QoL. Twenty responders continued the treatment. Afterwards, 8/20 (40%) discontinued therapy because of the following: losing response (2), progression to high-risk MDS (3) and death due to other causes (3). The remaining 12 are still responding and continuing treatment, with a median follow-up of 28 months. Progression to acute leukemia was cumulatively observed in 4/30 (13.3%) patients (2 in each arm). Although our data were obtained from a relatively small cohort of patients, they indicate that the rHEPO+G-CSF treatment is more effective than rHEPO alone for correcting anemia in low-risk MDS patients and for making a relevant improvement in their QoL.