We assessed the association between prenatal smoking and respiratory distress syndrome (RDS) among triplets using a population-based retrospective cohort of 12,169 triplet live births in the United States between 1995 and 1997. Analysis was conducted using the generalised estimating equation framework to adjust for intra-cluster correlations. A total of 938 cases of RDS were reported comprising 35 among smoking (7.2%) and 903 among non-smoking gravidas (7.7%). The likelihood of RDS was comparable in both smoking categories [adjusted odds ratio (OR) = 0.93; 95% confidence interval (CI) = 0.65-1.32]. The risk for RDS due to smoking diminished with declining birth weight albeit non-significantly: low birth weight (OR = 0.99; 95% CI = 0.40-2.42), very low birth weight (OR = 0.85; 95% CI = 0.39-1.86), and extremely low birth weight (OR = 0.69; 95% CI = 0.30-1.58). In conclusion, among triplet neonates, smoking during pregnancy was not associated with respiratory distress syndrome.