International shipping emissions (ISE), particularly sulfur dioxide, can influence the global radiation budget by interacting with clouds and radiation after being oxidized into sulfate aerosols. A better understanding of the uncertainties in estimating the cloud radiative effect (CRE) of ISE is of great importance in climate science. Many international shipping tracks cover oceans with substantial natural dimethyl sulfide (DMS) emissions. The interplay between these two major aerosol sources on cloud radiative effects over vast oceanic regions with relatively low aerosol concentration is an intriguing yet poorly addressed issue confounding estimation of the cloud radiative effects of ISE. Using an Earth system model including two aerosol modules with different aerosol mixing configurations, we derive a significant global net CRE of ISE (−0.153 W m −2 with p = 0.01 and standard error of 0.004 W m −2 ) when using emissions consistent with current ship emission regulations. This global net CRE would become much weaker and actually insignificant (−0.001 W m −2 with p = 0.98 and standard error of 0.007 W m −2 ) if a more stringent regulation were adopted. We then reveal that the ISE-induced CRE would achieve a significant enhancement when lower DMS emission is prescribed in the simulations, owing to the sub-linear relationship between aerosol concentration and cloud response. In addition, this study also demonstrates that the representation of certain aerosol processes, such as mixing states, can influence the magnitude and pattern of the ISE-induced CRE. These findings suggest a re-evaluation of the ISE-induced CRE with consideration of DMS variability.