BACKGROUND Several studies have demonstrated an increased risk of congenital hypothyroidism (CH) in girls in comparison to boys. OBJECTIVE The aim of this study was to determine the potential interactions that are able to change the effect of gender on congenital hypothyroidism. METHODS We conducted a matched 1:4 case-control study in Hamadan Province, western of Iran, from 2005 to 2011. Based on screening program data, neonates with TSH ≥ 10 mU/L and T4 ≤ 6.4 μg/dL were considered as congenital hypothyroidism (Cases). Cases and controls were matched regarding the year and place of birth. Data was analyzed using two different approaches including propensity score and multiple conditional logistic regression model. RESULTS A total of 277 cases and 1036 controls were included in the study. Girls accounted for 57.4% of the cases and 51.2% of controls (P = 0.065). Based on the multiple conditional logistic regressions, only the interaction of gender (girl) and birth season (summer) increased the likelihood of CH significantly (OR = 3.09; 95% CI: 1.09-8.74; P = 0.034). On the other hand, the ORs of the interaction of gender and all other factors (except for birth season) were not statistically significant in CH. CONCLUSIONS Birth season might act as an interaction that is able to increase the risk of CH in girls. Accordingly, awareness of the birth season could help policymakers who plan preventive programs to reduce the false negative results among neonates, especially girls.