Sulfolane is an organic solvent with a wide variety of industrial uses including sour gas sweetening, removal of hydrogen sulfide during shale and coal processing, the manufacture of polymers, electronics applications, and may also be found in pharmaceuticals as a residual contaminant remaining after the manufacturing process. Though sulfolane is not naturally occurring, it has been detected in groundwater near facilities where it has been used. Given the potential for human exposure (e.g., ingestion in drinking water, dermal contact during bathing and similar activities, and inhalation of sulfolane mist while showering) and the lack of any state or federal drinking water standards for sulfolane in the U.S., we employed benchmark dose (BMD) modeling to develop an oral reference dose (RfD) for sulfolane. Several studies involving oral exposures were identified and determined to be useful for development of toxicity benchmarks. Applying BMD modeling to several toxicological endpoints in these studies, RfD values ranging 0.012–0.037 mg/kg/day were calculated. The lower end of the range (0.01 mg/kg/day) was ultimately selected as the RfD in keeping with typical U.S. EPA practices. A drinking water screening level was subsequently developed based on this RfD using ingestion pathway equations and assumptions consistent with U.S. EPA’s Regional Screening Levels (RSLs). This resulted in a drinking water screening level of 365 ppb. As a screening level, this value incorporates conservative assumptions to ensure an ample margin of safety and, as such, this value cannot be viewed as a bright line for adverse health effects, but rather provides the public with a reasonable degree of confidence that concentrations at or below 365 ppb are unlikely to impact their health. In contrast, concentrations above 365 ppb would need to be evaluated more closely to determine the likelihood for adverse health effects.