Successful prevention of malaria is highly dependent on compliance with a prescribed daily chemoprophylaxis regimen. However, maintaining drug compliance by U.S. service members can be difficult due to a daily oral dosing requirement, side effects such as nausea and photosensitivity, organizational culture, command emphasis and the demands of the operational environment. The Experimental Therapeutics (ET) Branch at Walter Reed Army Institute of Research (WRAIR) is the U.S. Army’s premier research program for the development of anti-malarial prophylaxis drugs. A current effort of ET, in scientific collaboration with the Southwest Research Institute and Titan Pharmaceuticals, is to develop long-term release implantable anti-malarial drug matrices. These implants provide continuous drug release with non-fluctuating drug levels over an extended period and could potentially relieve deployed service members from adherence to a daily oral drug dosing schedule. EVA (ethylene-vinyl acetate) implants containing atovaquone, a compound effective against liver- and blood- stage malaria parasites, were tested in a mouse model with Plasmodium berghei to characterize the pharmacokinetic (PK) profile and long-term prophylactic efficacy in vivo. The atovaquone-containing implant study showed the PK profile exhibited slow drug release for sixteen weeks while maintaining stable plasma levels. Furthermore, after twelve weeks of implantation, the atovaquone implants demonstrated complete protection from infection by Plasmodium berghei parasites in mice. The development of long-acting prophylactic implants with greater potency and safety is a novel approach that could greatly improve the compliance of deployed service members in malaria-endemic regions. Furthermore, the target products will support the multi-domain battlefield operational concept by allowing ground combat forces to maneuver and perform in an uninterrupted manner in resource-constrained environments. These preliminary findings with atovaquone and doxycycline allow us to pursue a series of long-acting implants that include the FDA-approved anti-malarial drugs, combination atovaquone/proguanil (Malarone®) and doxycycline, for follow-on in vivo preclinical studies.