In this study, a desiccant-based hybrid cooling system supported by a vapor compression system and a heat recovery unit (rotary heat wheel) was analyzed from energetic and exergetic perspectives during the daily working hours of an office building in Istanbul to meet the desired comfort conditions. We focus on the impact of different refrigerants; namely R32, R1234yf, R290, R134a, R600a, R245fa, and R717, on hybrid rotary desiccant-vapor compression systems. While the highest electricity consumption was obtained in the system using R1234yf, the lowest electricity consumption was achieved with R717. However, with the effectiveness of the desiccant wheel, the best results were obtained for R1234yf with those pertinent to R717 at the other extreme. Considering the total electricity consumption of the system, the highest energetic and exergetic performance parameters were achieved with the use of R717 as the refrigerant. Compared to R1234yf, the daily average energetic performance parameters obtained with R717 increased by 22.3 % for COP _r, 21.8 % for COP _el, and 4.7 % for COP _th. Similarly, compared to R1234yf, the daily average exergetic performance parameters in R717 presented increases of 13.6 % for COP _x,el, 7.5 % for COP _x,th, and 8.1 % for η _x.