Rationale: Prenatal cigarette smoke exposure, increased environmental temperature and hypoxic episodes have been postulated as major risk factors for Sudden Infant Death Syndrome. Objectives: To test the hypothesis that maternal cigarette smoke exposure disrupts eupnic breathing and depresses breathing responses of neonatal rats to thermal and hypoxic challenges. Methods: Experiments were performed on one week old rat pups exposed prenatally to cigarette smoke (n = 39) or room air (sham; n = 30). Breathing patterns were recorded using whole-body plethysmography during thermoneutral or hyperthermic states under normoxic and hypoxic conditions. Measurements: Mean pup weight, breaths per minute and gasping respiratory patterns were measured for both smoke and sham exposed groups during thermoneutral and hyperthermic states under normoxic and hypoxic conditions. Main Results: Under thermoneutral conditions, hypoxia caused gasping in cigarette smoke exposed animals but not in sham animals. Furthermore, under hyperthermic conditions, while hypoxia induced gasping in both groups, only cigarette smoke exposed animals exhibited a pronounced and longer lasting respiratory depression following the termination of hypoxia. Conclusions: We show that prenatal cigarette smoke exposure increases the likelihood of gasplike respiration and provide the first experimental evidence that the combined effects of prenatal cigarette smoke exposure and hyperthermia dramatically prolong the time required for neonates to return to eupnic breathing following hypoxia. These observations provide important evidence of how prenatal cigarette smoke exposure, hypoxic episodes and hyperthermia might place infants at higher risk for Sudden Infant Death Syndrome.