To estimate the level of potentially preventable excess mortality achievable by avoiding the creation of higher-order multiple gestation with assisted reproductive technologies. This was a retrospective cohort study of multiple pregnancies delivered in the United States between 1995 and 1997 involving 304,466 twins, 16,068 triplets, 1448 quadruplets, and 180 quintuplets. We used the generalized estimating equation framework to compute adjusted relative risks for combined perinatal and infant mortality (early mortality). We then calculated potentially preventable excess mortality among higher-order gestations, using twins and triplets sequentially as the referent category. Early mortality increased significantly with each additional fetus in a dose-dependent fashion (P < .001), corresponding to relative risks (95% confidence interval) of 2.4 (2.2, 2.6) for triplets, 3.3 (2.5, 4.4) for quadruplets, and 10.3 (5.0, 21.4) for quintuplets. The creation of twin rather than quadruplet pregnancies would be associated with a substantially higher level of preventable excess mortality (70%) than the creation of triplet pregnancies (28%). By contrast, limiting quintuplets to twins or triplets did not exhibit a similar level of difference (89% versus 75%, respectively). Our findings support the need for regulating the number of transferred embryos that result in quadruplet and quintuplet pregnancies.