The effect of concanavalin A (ConA), phytohaemagglutinin P (PHA) and Limulus polyphemus haemocyanin (LPH) on the lethal activity of tetanus toxin (TT) is reported. C3H mice treated s.c. with ConA or PHA but not with LPH from 48 h before to 12 h after s.c. TT challenge showed a significant increase in median survival time compared to control mice inoculated with toxin alone. This protective effect was also obtained when PHA or ConA was administered by the i.p. route, TT being injected s.c. In further studies, mice treated with ConA or PHA by different routes (s.c., i.p. or i.v.) were challenged s.c. with graded minimal lethal doses of TT, with or without i.p. administration of horse antitetanus serum (HATS) 24 h after toxin inoculation. The mice treated with ConA or PHA + HATS showed a significantly increased survival rate and a higher percentage of cured mice with respect to control animals treated with lectins alone. In contrast, the mice challenged with TT and treated with HATS alone did not show any increased survival with respect to untreated controls. Sera from ConA- or PHA-treated mice were unable to neutralize the TT. Immune depression in mice by total-body irradiation (400 R) did not abolish the protective activity of the lectins. These results show that in vivo treatment of mice with ConA or PHA but not with LPH can protect against the lethal effects of TT.