The cost of nosocomial infections in the United States is estimated to be $4 billion to $5 billion annually. Applying a scientifically based analysis to disease transmission and performing a site specific risk analysis to determine the design of the ventilation system can provide real and long term cost savings. Using a scientific approach and convincing data, this paper hypothetically illustrates how a ventilation system design can be optimized to potentially reduce infection risk to occupants in an isolation room based on a thorough risk assessment without necessarily increasing ventilation airflow rate. A computational fluid dynamics (CFD) analysis was performed to examine the transport mechanism, particle path and a suggested control strategy for reducing airborne infectious disease agents. Most studies on the transmission of infectious disease particles have concentrated primarily on air changes per hour (ACH) and how ACH provides a dilution factor for possible infectious agents. Although increasing ventilation airflow rate does dilute concentrations better when the contaminant source is constant, it does not increase ventilation effectiveness. Furthermore, an extensive literature review indicates that not every exposure to an infectious agent will necessarily cause a recipient infection. The results of this study suggest a hypothesis that in an enclosed and mechanically ventilated room (e.g., an isolation room), the dominant factor that affects the transmission and control of contaminants is the path between the contaminant source and exhaust. Contaminants are better controlled when this path is uninterrupted by an air stream. This study illustrates that the ventilation system design,i.e., when it conforms with the hypothesized path principle, may be a more important factor than flow rate (i.e., ACH). A secondary factor includes the distance from the contaminant source. This study provides evidence and supports previous studies that moving away from the patient generally reduces the infection risk in a transient (coughing) situation, although the effect is more pronounced under higher flow rate. It is noted that future research is needed to determine the exact mode of transmission for most recently identified organisms.