Sub-Saharan Africa continues to bear a disproportionate burden of the global HIV epidemic. Conducting studies in the most affected areas of the world is critical to the international HIV research agenda. The Johns Hopkins University-Blantyre Clinical Trials Unit (JHU Blantyre-CTU) and its clinical research site (CRS) in Malawi, located in one of the most affected regions of the world, is continuing to expand high impact research collaborations with four NIAID HIV Clinical Research Networks in order to prevent, treat and manage HIV and AIDS in adults, couples and children. With more than 20 years of HIV research experience and the strong backing of the host institution, Johns Hopkins University, the CTU and CRS leadership is responsible for the coordination and execution of clinical trials at the Blantyre CRS in accordance with all Network, NIAID and regulatory policies. The CTU aims to advance the scientific agenda of the proposed Clinical Research Networks by generating and developing new scientific concepts; continuing implementation of the active study protocols at the CRS in Blantyre under the current CTU; and by having the capacity and processes in place to quickly engage protocol-specific research sites to respond to emerging Network needs. The CTU will emphasize quality, oversight, cohesiveness and efficiency in all operations as it works to achieve these aims. Currently, the Blantyre CRS is involved in 26 studies at various stages, from initiation to completion, for four existing Division of AIDS Clinical Research Networks. The CRS has established effective collaborations and engaged constituents representing the needs and research priorities of the local communities through the use of Community Advisory Group. We have developed and documented our administrative and financial management structures; plans for communication and evaluation; and the personnel and resources of each technical department of the Blantyre CRS, including community engagement, pharmacy, laboratory, quality and regulatory assurance, and data management.