Current research on human comfort has identified a gap in the investigation of multi-domain perception interactions. There is a lack of understanding the interrelationships of different physio-socio-psychological factors and the manifestation of their contextual interactions into cross-modal comfort perception. In that direction, this study used data from a post occupancy evaluation survey (n = 26), two longitudinal comfort studies (n = 1079 and n = 52) and concurrent measurements of indoor environmental quality factors (one building) to assess the effect of thermal, acoustic and air quality perception interactions on comfort and satisfaction of occupants in three mixed-mode university office buildings. The study concluded that thermal sensation (TSV) is associated with both air quality (ASV) and noise perception (NSV). The crossed effect of the interaction of air quality and noise perception on thermal sensation was not evident. The key finding was the significant correlation of operative temperature (T_op) with TSV as expected, but also with noise perception and overall acoustic comfort. Regarding the crossed main effects on thermal sensation, a significant effect was found for the interactions of (1) T_op and (2) sound pressure levels (SPL30) with air quality perception respectively. Most importantly, this study has highlighted the importance of air quality perception in achieving occupants’ comfort and satisfaction with office space.