The osmol gap can help detect and manage those with toxic alcohol exposure, and it is altered by all alcohols including ethanol. The optimal correction for ethanol that would allow accurate detection of an alternative alcohol is unclear.We conducted a prospective cohort study to assess baseline variations in osmol gap, and then to assess the validity of 2 commonly used coefficients (correction factors) for ethanol. Twenty-two healthy volunteers received a body mass-based dose of oral ethanol that targeted an estimated peak blood ethanol concentration >200 mg/dL. We measured laboratory values prior to ethanol administration and at 2, 4, and 6 hours after ingestion. We considered an osmol gap >10 or <-10 abnormal and an osmol gap of >10 after correction as a false positive.Four of the 22 subjects (18%) had an osmol gap >10 at baseline. Following ethanol ingestion and across 66 timepoints (N=66), there were 14 abnormal osmol gap tests (21%) when corrected with an ethanol coefficient of 4.6, and 31 (47%) abnormal tests when corrected using the Purssell ethanol coefficient of 3.7. The mean difference between the baseline and the post-ethanol corrected osmol gap was lower with the molecular weight correction factor of 4.6 compared with the Purssell correction factor of 3.7 (0.2 versus 11.0; P<.001).Our data show that the osmol gap is occasionally elevated absent ingestion of any alcohol, and using an ethanol correction coefficient of 4.6 produced a better clinical osmol gap input albeit still with some variation.