Rationale: The effects of prenatal cigarette smoke exposure and hypoxemia on cardio-respiratory control have been investigated in full term infants. However, little data are available in preterm infants, who form a particularly vulnerable population, with developmentally immature cardiorespiratory control. Objectives: To investigate the effects of prenatal cigarette smoke exposure on the duration and recovery of breathing pauses and oxygen saturation levels under baseline and hypoxemic conditions in preterm infants. Methods: The study was performed on twenty two (12 born to smoking and 10 to non-smoking mothers) spontaneously breathing preterm infants between 28-36 weeks gestation. Cardiorespiratory variables were recorded under baseline normoxemic and hypoxemic conditions. Measurements: Breathing pauses, pause indices, time to recovery, percent pause recovery, oxygen saturation (SpO₂), periods of wakefulness and cardiorespiratory rates were compared between the two groups. Main Results: Spontaneous recovery of breathing pauses (P = 0.03) and SpO₂ levels (P = 0.017) were attenuated in cigarette smoke exposed infants as compared with the control group during the hypoxemic and post-hypoxemic periods, respectively. The episodes of wakefulness during the hypoxemic challenge were similar between the two groups. Furthermore, cigarette smoke exposed infants showed a greater increase in heart rate (P < 0.001) during the hypoxemic challenge when compared to control infants. Conclusions: We provide evidence of how prenatal cigarette smoke exposure and hypoxemic episodes affect the duration and recovery of breathing pauses in preterm infants. These observations could help explain why these infants are at a particularly high risk for Sudden Infant Death Syndrome.