Abstract This study examined the thermodynamic effects of relative humidity (RH) on the performance of the natural gas liquefaction process. A single mixed refrigerant (SMR) liquefaction process was chosen for this study because of its simplicity and compactness. In addition, it is considered the most promising process for the liquefied natural gas (LNG) floating production, storage and offloading (FPSO) unit. The SMR process was optimized using a modified coordinate descent methodology, which resulted in 13.6% energy savings. Subsequently, an interface between commercial software Aspen Hysys® and MS-Excel VBA was carried out to study the effects of RH. The results showed that RH has pronounced effects on the performance of the LNG cycle by affecting the enthalpy balance around the air coolers, which ultimately affects the overall compression power, LNG exchanger performance, and other design and operational parameters. Furthermore, when the RH was increased from 0% to 95%, the UA value (product of overall heat transfer coefficient and heat transfer area) of the air coolers and the overall compression power decreased and increased linearly, respectively. Moreover, the heat transfer coefficient of the LNG cryogenic exchanger increased as a 4th order polynomial function in terms of the log-mean enthalpy difference. The results can provide insight into the selection of the appropriate design and operational parameters for the LNG plants associated with the regions of low or high relative humidity.