Background: The number of peripherally inserted central catheter (PICC) lumens is associated with thrombotic and infectious complications. Because multilumen PICCs are not necessary in all patients, policies that limit their use may improve safety and cost. Objective: To design a simulation-based analysis to estimate outcomes and cost associated with a policy that encourages single-lumen PICC use. Methods: Model inputs, including risk of complications and costs associated with single- and multilumen PICCs, were obtained from available literature and a multihospital collaborative quality improvement project. Cost savings and reduction in central line-associated bloodstream infection and deep vein thrombosis events from institution of a single-lumen PICC default policy were reported. Results: According to our model, a hospital that places 1,000 PICCs per year (25% of which are single-lumen and 75% multilumen) experiences annual PICC-related maintenance and complication costs of $1,228,598 (95% CI, $1,053,175-$1,430,958). In such facilities, every 5% increase in single-lumen PICC use would prevent 0.5 PICC-related central line-associated bloodstream infections and 0.5 PICC-related deep vein thrombosis events, while saving $23,500. Moving from 25% to 50% single-lumen PICC utilization would result in total savings of $119,283 (95% CI, $74,030-$184,170) per year. Regardless of baseline prevalence, a single-lumen default PICC policy would be associated with approximately 10% cost savings. Findings remained robust in multiway sensitivity analyses. Conclusion: Hospital policies that limit the number of PICC lumens may enhance patient safety and reduce healthcare costs. Studies measuring intended and unintended consequences of this approach, followed by rapid adoption, appear necessary.