The critical aspects of the impact of microbiological contamination on ventilation and air conditioning systems, the microclimate of the premises, and human health are analyzed. The quantitative and qualitative composition of the microflora of premises depends on their functional purpose, design features, operating conditions, climate, and other factors, among which the method of ventilation is essential. The moisturizers in the air conditioning system are hazardous, which provide bacteria and fungi with water necessary for their life and reproduction. In addition, contaminants accumulated in ventilation systems operate as a substrate for feeding microorganisms. Multi-story administrative, public, and residential buildings, industrial buildings, and other places of mass concentration are areas of increased aerobiological risk of infection. In case of improper operation, air conditioning and ventilation systems can be sources of microorganisms in any room. Transmission of infectious aerosol over long distances occurs in rooms with poor ventilation, and a key factor for the outbreak of infection is the direction of airflows. In the context of the COVID-19 pandemic, organizations and international agencies to control the spread of SARS-CoV-2 indoors recommend limiting the operation of exhaust ventilation and recirculation systems. However, there is still insufficient data to clarify the role of heating, ventilation, and air conditioning systems in spreading infection. Risk assessment and decision-making on the choice of air conditioning systems should be dynamic and based on the scale of the pandemic and the verification of the characteristics of HVAC systems and their effectiveness.