Central line-associated bloodstream infection is a preventable contributor to excess death and excess cost in the health care system. Vasopressor infusion is one of the primary reasons for central line placement. In the medical intensive care unit (MICU) at an academic medical center, there was no standard practice for peripheral versus central infusion of vasopressors. The objective of this quality improvement project was to implement an evidence-based, nurse-driven protocol to guide the peripheral infusion of vasopressors. The goal was to reduce central line utilization by 10%. Education on the protocol was provided to the MICU nurses, MICU residents, and crisis nurses, followed by a 16-week implementation period. Nursing staff were also surveyed preimplementation and postimplementation of the protocol. Central line utilization was reduced by 37.9%, and there were no central line-associated bloodstream infections recorded during project implementation. Most of the nursing staff indicated that use of the protocol increased their confidence in administering vasopressors without a central line. No significant extravasation events occurred. Although a causal link between implementation of this protocol and reduction of central line utilization cannot be established, the reduction is clinically meaningful given the known risks of central lines. Increased nursing staff confidence also provides support for continued use of the protocol. A nurse-driven protocol to guide the peripheral infusion of vasopressors can be effectively implemented into nursing practice.