Recent evidence suggests that the susceptibility to respiratory distress syndrome (RDS) is partly explained by genetic variation in the surfactant proteins (SP) SP-A and SP-B. The present study was designed to evaluate the concordance difference method and candidate gene analysis, in parallel, for the investigation of genetic susceptibility to RDS. We studied 100 same-sex twin pairs with established RDS in at least one twin. The difference in RDS concordance rates between the monozygotic (MZ) and dizygotic (DZ) twin pairs as evidence of a genetic influence was evaluated, and the SP-A and SP-B genes were investigated for potential associations with the susceptibility to RDS. The concordance rates of RDS were 54 and 44% in the MZ and DZ pairs, respectively. The concordance difference of 10% was not significant [95% confidence interval (CI) -0.1 to +0.3, P=0.32], suggesting a low hereditary impact. However, the SP-B Ile131Thr polymorphism was associated with RDS. The threonine allele was associated with an increased risk of RDS [odds ratio (OR) 2.2, 95% CI 1.4-3.5, P=0.0014]. This was particularly apparent in first-born male infants (OR 6.2, 95% CI 2.4-16.3, P