The virulence of Salmonella typhi is associated with the presence of the Vi antigen. Mechanisms of Vi antigen virulence were examined in vitro. The Vi antigen-containing strain Quailes was significantly (P less than 0.025) more resistant to lysis by nonimmune serum than S. typhi 0901, which does not have the Vi antigen, and resulted in less activation of complement by the alternative pathway (P less than 0.05). Human polymorphonuclear leukocytes (PMNs) ingested strain Quailes significantly (P less than 0.01) more slowly and less completely than strain 0901 as assessed by three measures of phagocytic rate. In contrast to prior reports, the Vi antigen did not prevent an oxidative burst, measured by O2- production, chemiluminescence, and O2 consumption. The extent of the oxidative burst correlated directly and closely with the rate of phagocytosis. When the rate of PMN phagocytosis for both strains was equalized by opsonizing strain 0901 with 1% and strain Quailes with a 3% concentration of serum, the PMN oxidative burst was equal. C3 binding to strain Quailes was significantly (P less than 0.005) less than to strain 0901. Hence the Vi antigen inhibited phagocytosis by preventing C3b binding and solely as a consequence of this induced a lesser PMN oxidative burst. Furthermore, strain Quailes was significantly (P less than 0.025) less susceptible to killing by H2O2 than strain 0901. To ensure that these observations were a consequence of the Vi antigen and not other strain differences, another pair of S. typhi with and without the Vi antigen were similarly compared, and the results were the same as with strains Quailes and 0901. Strains 0901 and Quailes were killed by PMNs from a patient with chronic granulomatous disease but more slowly than by normal PMNs, indicating that S. typhi is susceptible to nonoxidative killing.