With the introduction of tandem mass spectrometry, newborn screening for disorders of propionate metabolism became widely available. However, there is controversy whether population screening for these disorders should be performed. The most widely used primary metabolite C3 itself has a poor specificity or lacks 100% sensitivity for milder forms and/or defects of cobalamin metabolism. Strategies to improve specificity have included the calculation of metabolite ratios (e.g. C3/C2) or second-tier strategies with analysis of methylmalonic acid or 2-methylcitric acid from the primary screening specimen. We report the results of a new statistical approach to identify parameter combinations that allow for 100% sensitivity as well as increased specificity. The promising results of this alternative approach will have to be substantiated on larger data sets.