The effect of structural modifications of 6-substituted N-(1H-tetrazol-5-yl)-2-pyrazinecarboxamides on their anti-allergic activity was analyzed quantitatively by means of the Hansch-Fujita method. The activity of these compounds was correlated with hydrophobic (pi) and steric (molecular refractivity and STERIMOL B1) effects of the 6-substituent on the pyrazine ring. The 6-substituents with a length greater than n-propylamino possess an extra effect enhancing the activity. Moreover, the activity increased progressively from 6-non-amino via alkylamino- to dialkylamino-substituted compounds, other factors being equal. This could be attributable to an electronic effect of substituents. Electron-donating small and yet symmetric substituents with high hydrophobicity longer than n-propylamino seemed to be favorable to the activity. By compromising these contradictory requirements, small dialkylamino (including cyclic amino) groups were decided to be the most favorable substituents. This analysis was in agreement with the observation that the most effective compounds were the 6-dimethylamino (I-27) and 6-(1-pyrrolidinyl) (I-34) derivatives.