Introduction: Based on many scientific research studies, there has been demonstrated a relation between smoking of pregnant women and its negative effects on pregnancy, intrauterine fetal growth, postnatal newborn condition, and development. The aim of our study is to highlight the adverse effects of cigarette use during pregnancy and to evaluate the effect of maternal smoking on the levels of erythropoietin (EPO) in umbilical cord plasma. Our aim was to show an effect of maternal smoking by determining carboxyhemoglobin (COHb) levels in maternal blood, too. Design: Prospective analysis. Setting: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University, Martin, Slovak Republic. Methods: Our study included 174 newborns. Mothers were divided into group of smokers (n = 67) and non-smokers (n = 107). This prospective study was realized from February 2012 to November 2013 at the Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Slovak Republic. Patients signed a written informed consent and completed a questionnaire that involved medical history, and data of their smoking habits. EPO levels were measured in 174 samples of umbilical cord plasma. Infants were born spontaneously at term. Results: We observed significantly higher EPO levels in umbilical cord plasma in children born to smokers in contrast to non-smokers’ (children of non-smoking mothers: 19 ± 8 mIU/mL; children of smokers: 61 ± 33 mIU/mL, p < 0.01). The COHb levels were significantly higher in smokers (non-smokers: 0.8% ± 0.4%; smokers: 3.6% ± 1.1%, p < 0.001). Conclusion: Smoking during pregnancy is associated with elevated EPO concentrations in umbilical cord plasma at the time of birth. Based on the results of our study, we would like to support women planning pregnancy and pregnant women to quit smoking. Closer surveillance is recommended in smoking pregnant women, particularly because of the risk of placental insufficiency and fetal growth retardation.