The rate for musculoskeletal injuries among health care workers is one of the highest for all industrial sectors in the United States; these injuries often occur during manual handling (i.e., lifting, moving, transferring, and repositioning) of patients. The following article describes the process used to complete a comprehensive assessment, as well as the planning, implementation, and initial evaluation of a quality improvement program to reduce work-related musculoskeletal disorders (WMSD) among health care workers employed by a rural Midwest hospital. Key elements for WMSD injury reduction were identified and compared across literature sources, national standards, and current state and federal legislative requirements for hospitals. The program used a multi-factor design that included evidence-based interventions (i.e., those supported by emerging evidence) to create a comprehensive Safe Patient Handling and Mobility (SPHM) program intended to address the unique needs of the organization. Initial program results are reviewed as well as significant considerations and challenges for SPHM programs.