The lipopolysaccharide of Salmonella is an important virulence factor; loss of its a-specific side chains results in loss of virulence. We have examined the effect of qualitative alterations of the O side chains by determining the ld50 values of Salmonella typhimurium derivatives after intraperitoneal infection of the mouse. Isogenic transductants were most virulent if the a antigen was 1,4,12, less virulent when the O antigen was 1,9,12, and nearly avirulent when the O antigen was 6,7. Modifications of the 4,12 type (antigen factors 1, 5, or 122) did not affect virulence [1]. The 4,12 and 9,12 lipopolysaccharides of the transductants, although quantitatively similar [2], differ qualitatively: 4,12 has abequose in the position where 9,12 has another dideoxyhexose, tyvelose. How then does the mouse discriminate between these two very similar structures in a way that leads to the observed difference in virulence? So far we have obtained no evidence that either the immune system or the phagocytic defenses account for this difference. Suppression of immune responses did not alter the discrimination [3], and the 4,12 and 9,12 types survived to the same extent inside peritoneal macrophages of mice.