During a recent International Space Station (ISS) flight (Flight 2A.1), an improper ventilation event might have occurred and resulted in stuffy air, as reported by the crew. Even though no air samples were analyzed, the accumulation of metabolic CO2 in the ISS was suspected as the cause of the crew sickness. With no possibility of conducting an on-orbit test of this kind, it was decided to utilize Computational Fluid Dynamics (CFD) analysis to investigate this problem. Based on the Flight 2A.1 and 2A.2a configurations, a CFD model of the air distribution system was built to characterize airflow between the ISS elements. This model consists of Inter-module Ventilation (IMV) covering the Functional Cargo Block (FGB), two Pressurized Mating Adapters (PMA-1 and PMA-2), the Node-1, and portions of the Orbiter volume. Several Environmental Control and Life Support System (ECLSS) steady-state operating scenarios were simulated to understand the airflow patterns and temperature distributions in the ISS. The preliminary results indicated that there is a lack of proper air exchange between the FGB module and the rest of the ISS. Therefore, the cool fresh air from the Orbiter will have difficulty diffusing into the FGB via Node-1 and PMA-1. To simulate the crew activities in the FGB, the CFD model is able to present the various combinations of airflow blockage in the aisle-way. This capability would further examine ventilation effectiveness of future flight configurations. The study of CO2 accumulation in the ISS is accomplished by simulating the generation and the transport of CO2 due to the metabolic sources of the crew and the blockage or disruption of the airflow path, especially in the FGB module.