Objective: To assess the association between the use of medically assisted reproduction (MAR) and birth defects (BD) in newborns and terminations of pregnancy in pregnant women registered in Barcelona in the period 1992 to 2007. Methods: We studied 1905 cases and 2722 controls in a retrospective population-based case-control study. Cases comprised any newborn presenting at least one major BD, as well as any pregnancy terminated because of BD. Controls were newborns without BD. Exposure was MAR. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were calculated by means of logistic regression to assess the association. Results: The MAR was demonstrated to be associated with BD, after adjusting for probable confounders (aOR=1.8; 95% CI=1.4 to 2.5). Regarding MAR modalities, this association was statistically significant only for assisted reproduction techniques (ART) (aOR=2.7; 95% CI=1.8 to 4.1). In the stratified analysis by structural BD categories, frequencies for all categories were increased after ART with the exception of head-face-neck-eye defects, none after artificial insemination, and digestive-abdominal wall defects in ovulation induction. Conclusions: This study demonstrated a strong association between ART and BD, with an almost threefold increased risk for overall BD after ART, as compared with natural conception. Increased associations were also observed for almost all structural BD categories. © 2013 John Wiley & Sons, Ltd.