Background: The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy. Objective: We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG. Methods: In 3 of 4 protocols (A, B, and C), MSG was administered without food. A positive response was scored if the subject reported 2 or more symptoms from a list of 10 symptoms reported to occur after ingestion of MSG-containing foods within 2 hours. In protocol A 130 self-selected reportedly MSG-reactive volunteers were challenged with 5 g of MSG and with placebo on separate days (days 1 and 2). Of the 86 subjects who reacted to MSG, placebo, or both in protocol A, 69 completed protocol B to determine whether the response was consistent and dose dependent. To further examine the consistency and reproducibility of reactions to MSG, 12 of the 19 subjects who responded to 5 g of MSG but not to placebo in both protocols A and B were given, in protocol C, 2 challenges, each consisting of 5 g of MSG versus placebo. Results: Of 130 subjects in protocol A, 50 (38.5%) responded to MSG only, 17 (13.1%) responded to placebo only (P < .05), and 19 (14.6%) responded to both. Challenge with increasing doses of MSG in protocol B was associated with increased response rates. Only half (n = 19) of 37 subjects who reacted to 5 g of MSG but not placebo in protocol A reacted similarly in protocol B, suggesting inconsistency in the response. Two of the 19 subjects responded in both challenges to MSG but not placebo in protocol C; however, their symptoms were not reproducible in protocols A through C. These 2 subjects were challenged in protocol D 3 times with placebo and 3 times with 5 g of MSG in the presence of food. Both responded to only one of the MSG challenges in protocol D. Conclusion: The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion are observed, and the responses were not consistent on retesting. (J Allergy Clin Immunol 2000;106:973-80.)