Using atypical symptoms at presentation as red flags to indicate an alternative diagnosis to MS has not been formally assessed. The purpose of this study was to assess the utility of defining the typicality and atypicality of symptoms at presentation in the diagnosis of patients referred as being “query MS”. A 3-year review of patients referred as “query MS” was performed. Patients were classified on the basis of the first clinical assessment as having typical symptoms of MS or atypical symptoms suggesting an alternative diagnosis. The initial clinical opinion was correlated with the eventual diagnosis. Raters blinded to the diagnosis also assigned typical or atypical status to the patients. 247 patients were referred with suspected MS. 56% had MS and 44% did not. 129 patients had atypical symptoms of whom, 81% did not have MS; 98 patients had typical symptoms; 10% did not have MS. Atypical symptoms had a sensitivity of 85% and specificity of 87% for the diagnosis of “not MS”. Positive predictive and negative predictive values were 90% and 81% respectively. Atypical features as indicators of not MS have a high sensitivity and specificity.