COVID-19 and its impact on society have raised concerns about scaling up mechanical ventilation (MV) systems and the energy consequences. This paper attempted to combine MV and portable air cleaners (PACs) to achieve acceptable indoor air quality (IAQ) and energy reduction in two scenarios: regular operation and mitigating the spread of respiratory infectious diseases (RIDs). We proposed a multi-objective optimization method that combined the NSGA-II and TOPSIS techniques to determine the total equivalent ventilation rate of the MV-PAC system in both scenarios. The concentrations of PM
2.5
and CO
2
were primary indicators for IAQ. The modified Wells-Riley equation was adopted to predict RID transmissions. An open office with an MV-PAC system was used to demonstrate the method’s applicability. Meanwhile, a field study was conducted to validate the method and evaluate occupants’ perceptions of the MV-PAC system. Results showed that optimal solutions of the combined system can be obtained based on various IAQ requirements, seasons, outdoor conditions, etc. For regular operation, PACs were generally prioritized to maintain IAQ while reducing energy consumption even when outdoor PM
2.5
concentration was high. MV can remain constant or be reduced at low occupancies. In RID scenarios, it is possible to mitigate transmissions when the quanta were < 48 h
−1
. No significant difference was found in the subjective perception of the MV and PACs. Moreover, the effects of infiltration on the optimal solution can be substantial. Nonetheless, our results suggested that an MV-PAC system can replace the MV system for offices for daily use and RID mitigation.
Electronic Supplementary Material (ESM)
The Appendix is available in the online version of this article at 10.1007/s12273-023-0999-z.