Background: Sudden Infant Death Syndrome (SIDS) is one of the most common causes of post-natal infant mortality in the developed world. Identified risk factors for SIDS include prenatal cigarette smoke exposure, hyperthermia and infection, but the mechanisms underlying SIDS remain elusive. Objective: To examine if prenatal cigarette smoke (CS) exposure, lipopolysaccharide (LPS)-induced infection and environmental temperature interact to alter cardio-respiratory outcomes of neonatal rats before, during or after hypoxia. Methods: During the gestational period dams were treated daily with CS. Sham treatments were performed in parallel. Offspring were studied at postnatal day 6-8 (11-20g). These neonates were examined under both thermoneutral (33°C) and hyperthermic (38°C) conditions. Within each group, rats were allocated to control, saline or LPS (200µg/kg I.P.) treatments. Cardio-respiratory pattern was examined using head-out plethysmography and ECG before, during and after hypoxic stress (10% O2). Body surface temperature was monitored throughout the experiments Results: Two hours post LPS administration, body temperature was not different compared to sham, in rats studied at 33°C (P=0.9995; One-way ANOVA) and 38°C (P=0.8272; One-way ANOVA); n=10-13. Heart rate (HR) was analysed using 3-way ANOVA (smoke x LPS x temperature; n=10-13), during last minute of baseline, hypoxia and post hypoxic periods. Prenatal CS did not significantly alter HR by itself (P=0.18) nor did it interact with infection (P=0.88) or high temperature (P=0.61). Hyperthermia increases HR during normoxia (P<0.0001) and even further during hypoxia (P<0.0001). Mild infection in a high temperature environment increases HR during normoxia (P=0.043) and blunts normal hypoxic response (P=0.033). In the post hypoxic period, neonatal rats at 33°C had significantly lower HR than their initial baseline rate, compared to those rats at 38°C (P<0.001). Under thermoneutral, but not hyperthermic conditions, there was an increased number of apnoea’s in prenatal CS exposed rats compared to sham in the post hypoxic period (P=0.0015; two way ANOVA smoke x LPS; n=10-13), LPS had no effect on apnoea count in thermoneutral (P=0.8219) or hyperthermic conditions (P=0.6559). Under high temperature conditions minute ventilation in LPS-treated neonates was significantly higher than saline treated rats post hypoxia (P=0.0214; two-way ANOVA smoke x LPS; n=6). Conclusion: Multiple risk factors may interact in a hyper additive manner (eg. increased heart rate during high temperature in animals with mild LPS-induced infection). It is important we understand these interactions in the context of SIDS. However, it is clear that environmental risk factors predominately increase work rate of cardio-respiratory system in the neonatal rat. This may lead to overburden and instability of the system.