Objective: We sought to evaluate 17-alpha-hydroxyprogesterone caproate (17P) for prevention of preterm birth (PTB) in women with prior spontaneous PTB (SPTB) and cervical length (CL) <25 mm. Study Design: We conducted planned secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development-sponsored randomized trial evaluating cerclage for women with singleton gestations, prior SPTB (17-33 6/7 weeks), and CL <25 mm between 16-22 6/7 weeks. Women were stratified at randomization to intent to use or not use 17P. The effect of 17P was analyzed separately for cerclage and no-cerclage groups. Primary outcome was PTB <35 weeks. Results: In 300 women, 17P had no effect on PTB <35 weeks in either cerclage (P = .64) or no-cerclage (P = .51) groups. Only PTB <24 weeks (odds ratio, 0.08) and perinatal death (odds ratio, 0.14) were significantly lower for those with 17P in the no-cerclage group. Conclusion: 17P had no additional benefit for prevention of PTB in women who had prior SPTB and got ultrasound-indicated cerclage for CL <25 mm. In women who did not get cerclage, 17P reduced previable birth and perinatal mortality. © 2010 Mosby, Inc. All rights reserved.