In a multiple-challenge study of US adult volunteers with low or high levelsof serum antibody to Norwalk virus, Norwalk inoculum 8FIIa was administered to 42 subjects, 22 were challenged 6 months later, and 19received a third challenge after 6 more months. All 12with high (⩾1:200) but only 19of 30 with low <1:100) prechallenge titers experienced illness or a fourfold increase in titer after the first challenge (P<.025). Only 4 of those challenged twice became ill; all had low initial titers but 3 had high titers before the second challenge. None became ill after a third challenge. Nine (47%) had high titers immediately before the third challenge; 3 had low titers before and after each challenge and remained asymptomatic. Thus, preexisting serum antibody to Norwalk virus does not seem to be associated with protective immunity, but antibody levels become associated with protection after repetitive exposure. Short-term resistance lasts ⩾6 months after challenge, and a small percentage of resistant individuals maintain low antibody titers even after multiple challenges.