Purpose: There are so many causes of an altered mental status, including acute stroke and nonorganic causes. Making the differential diagnosis and the diagnostic approach for cases with an altered mental status represent a challenge to all emergency physicians. The serum S-100B protein concentration and the neuron-specific enolase (NSE) concentration have been used to evaluate brain damaged patients. We evaluated the usefulness of the serum S-100B protein concentration and the NSE concentration as screening tests for the patients with an altered mentality Methods: Seventy-eight patients with an altered mentality were included in this prospective study. The patients were divided in two groups. One was the acute stroke group and the other was the non-organic cause group. We analyzed the serum S-100B protein and NSE concentrations of the two groups. We also assessed the correlation of the serum S-100B protein and NSE concentrations with the clinical and laboratory data of the two groups Results: The serum concentration of S-100B was higher in the acute stroke group (median: 0.376, interquartile range: 0.18-1.05) than that in the nonorganic group (0.123, 0.087-0.307, p=0.000). The NSE level was also higher in the acute stroke group (median: 19.12, interquartile range: 14.42-27.19) than that in the non-organic group (13.71, 10.48-19.29, p=0.002). To differentiate the acute stroke group from the non-organic group, the sensitivity and specificity was 81.1% and 61.0%, respectively, at a cutoff value for the serum S-100B protein concentration of 0.14 ㎍/L, and these were 81.1% and 51.2%, respectively, at a cutoff value for the serum NSE concentration of 13.71 ㎍/L Conclusion: Our study suggests that the serum S-100B protein and NSE concentrations may be useful as screening markers for differentiating acute stroke from non-organic causes. However, further studies are needed to evaluate the relationship between the two proteins and the various diseases that have possibility to alter patients` mental status before these two proteins can be used clinically as screening tests.