Preterm birth (PTB) contributes significantly to infant mortality and morbidity with lifelong impact. Few robust genetic factors of PTB have been identified. Such 'missing heritability' may be partly due to gene x environment interactions (G x E), which is largely unexplored. Here we conduct genome-wide G x E analyses of PTB in 1,733 African-American women (698 mothers of PTB; 1,035 of term birth) from the Boston Birth Cohort. We show that maternal COL24A1 variants have a significant genome-wide interaction with maternal pre-pregnancy overweight/obesity on PTB risk, with rs11161721 (PG x E=1.8 x 10-8; empirical PG x E=1.2 x 10-8) as the top hit. This interaction is replicated in African-American mothers (PG x E=0.01) from an independent cohort and in meta-analysis (PG x E=3.6 x 10-9), but is not replicated in Caucasians. In adipose tissue, rs11161721 is significantly associated with altered COL24A1 expression. Our findings may provide new insight into the aetiology of PTB and improve our ability to predict and prevent PTB.