© 2017 American Sexually Transmitted Diseases Association All rights reserved. Background: High rates of failure to qualify for clinical trial participation increase time and cost required for study completion. Identification of remediable reasons for prescreen failure can help reduce prescreen failure rates and improve study cost effectiveness. Methods: Reasons for prescreen failure to qualify for participation in a phase 2 randomized clinical trial of treatment of uncomplicated urogenital gonorrhea were collected from prescreening logs. Reasons were categorized based on whether the reason was that the subject failed to meet eligibility criteria or declined participation. Subjects who failed prescreening but could have been enrolled under protocol amendments were used to estimate potential cost savings had enrollment completed sooner. Results: Over 88% (1373/1554) of potential study candidates were not enrolled. The majority (68.8%) of nonenrolled subjects failed prescreening due to not meeting eligibility criteria, whereas 31.0% declined to participate. The most common reasons for failure to qualify were having only nonurogenital gonorrhea (16.4%), limited time (13.1%), and being on antiretroviral therapy (7.5%). Potential cost savings if protocol amendments affecting eligibility had been instituted earlier were estimated at US 127,500. Conclusions: Careful attention to reasons for prescreen failure can inform clinical trial protocol development to address trial design features that may impact successful enrollment. More efficient subject enrollment can result in substantial cost savings.