Practices of knowledge management are context-specific and they can influence organizational effectiveness. This study examines the possible mediating role of knowledge management in the relationship between organizational culture, structure, strategy, and organizational effectiveness. A survey was conducted of 301 organizations. The results suggest that knowledge management fully mediates the impact of organizational culture on organizational effectiveness, and partially mediates the impact of organizational structure and strategy on organizational effectiveness. The findings carry theoretical implications for knowledge management literature as they extend the scope of research on knowledge management from examining a set of independent management practices to examining a system-wide mechanism that connects internal resources and competitive advantage.