U.S. Food and Drug Administration (FDA)-approved 17α-hydroxyprogesterone caproate therapy is currently available to reduce recurrent preterm birth in the United States. This commentary reviews the original landmark Meis trial ("Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate"), which led to conditional approval of 17α-hydroxyprogesterone caproate by the FDA in 2011. The recent PROLONG (Progestin's Role in Optimizing Neonatal Gestation) trial failed to confirm the original findings. The Meis trial was rigorously designed and conducted, with highly statistically significant results that should not be undermined by the negative results of PROLONG. Given that the United States has among the highest preterm birth rates in the world and that the predominant enrollment in PROLONG was outside the United States, the results of the "old" Meis trial should not be summarily dismissed. It would be detrimental to high-risk pregnant patients to inappropriately prioritize results of PROLONG over the Maternal-Fetal Medicine Units Network's Meis trial (funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development). We assert PROLONG was underpowered, based on substantially lower observed preterm birth rates than anticipated, and therefore was a false-negative study, rather than the Meis trial being a false-positive study. Careful assessment of these two trials is critical as removal of 17α-hydroxyprogesterone caproate from the U.S. marketplace may have substantial effects on public health.