BACKGROUND AND AIM: Previous research suggests gestational exposure to particulate matter ≤ 2.5 μm (PM2.5) and extreme heat may independently increase risk of birth defects. We investigated whether duration of gestational extreme heat exposure modifies the associations between PM2.5 exposure and specific congenital heart defects (CHDs). METHODS: We identified live-birth, stillborn, and induced termination CHD cases (n = 2,824) and non-malformed live-birth controls (n = 4,033) from pregnancies ending between October 1997 and December 2011 in the National Birth Defects Prevention Study (NBDPS). We assigned mothers 6-week averages for 24-hour PM2.5 exposure during the cardiac critical period (gestational weeks 3-8) using the closest monitor within 50 kilometers of maternal residence. We assigned a count of extreme heat days (EHDs, days above the 90th percentile from daily maximum temperature distribution for region, year, and season) during this period using the closest weather station. Using generalized additive models (GAMs), we explored logit-nonlinear exposure-outcome relationships, observing that linearity assumptions were reasonable. We estimated joint effects of PM2.5 and EHDs on six CHDs using logistic regression models adjusted for critical period regional mean dewpoint and maternal age, education, and race/ethnicity. In final models, we assessed multiplicative and additive effect modification. RESULTS:In adjusted models, conditional on mothers experiencing the highest observed EHD count (17), each 5 μg/m³ increase in average PM2.5 exposure was associated with increased odds of any septal defect (OR: 1.52 [95% CI: 1.04, 2.23]) and perimembranous ventricular septal defects (OR: 1.68 [95% CI: 1.02, 2.83]). Associations conditional on low/median maternal EHDs were null or inverse. Multiplicative and additive effect modification estimates were consistently positive when considering septal defects. CONCLUSIONS:Results suggest cumulative extreme temperature exposure during early pregnancy may modify associations between PM2.5 and some CHDs. Specifically, maternal extreme heat and PM2.5 exposure may jointly increase risk of offspring septal defects. Abstract does not represent EPA/CDC policy. KEYWORDS: particulate matter, temperature extremes, birth outcomes, cardiovascular diseases