Air quality models are typically used to predict the fate and transport of air emissions from industrial sources to comply with federal and state regulatory requirements and environmental standards, as well as to determine pollution control requirements. For many years, the U.S. Environmental Protection Agency (EPA) widely used the Industrial Source Complex (ISC) model because of its broad applicability to multiple source types. Recently, EPA adopted a new rule that replaces ISC with AERMOD, a state-of-the-practice air dispersion model, in many air quality impact assessments. This study compared the two models as well as their enhanced versions that incorporate the Plume Rise Model Enhancements (PRIME) algorithm. PRIME takes into account the effects of building downwash on plume dispersion. The comparison used actual point, area, and volume sources located on two separate facilities in conjunction with site-specific terrain and meteorological data. The modeled maximum total period average ground-level air concentrations were used to calculate potential health effects for human receptors. The results show that the switch from ISC to AERMOD and the incorporation of the PRIME algorithm tend to generate lower concentration estimates at the point of maximum ground-level concentration. However, the magnitude of difference varies from insignificant to significant depending on the types of the sources and the site-specific conditions. The differences in human health effects, predicted using results from the two models, mirror the concentrations predicted by the models.