The capacity of tetanus toxin to enhance motor neuron excitability has suggested its potential use as a therapeutic. Widespread active vaccination against tetanus in all developed countries is considered the major obstacle to clinical use of the toxin. We wished to determine the response to localized intramuscular injection of tetanus toxin in both passively and actively immunized animals as an initial exploration into the possible use of tetanus toxin as a clinical therapeutic. Unvaccinated mice (n=18) underwent intramuscular injection of tetanus toxin into the gastrocnemius muscle (0.2 ng, 1 ng, 5 ng). All animals in the lowest dose group developed only local tetanus of the injected limb of at least 2 weeks duration, while all animals in the higher dose groups also rapidly developed generalized tetanus and were euthanized. Another group of mice (n=20) received anti-tetanus immunoglobulin (20-40 IU) at the time of toxin injection. These animals although dramatically resistant to the toxin developed predominantly local tetanus for over one month at doses of 2.5 microg and 5.0 microg. A third group of mice (n=30) underwent active vaccination with tetanus toxoid to induce protective anti-tetanus immunity and then was challenged with high dose toxin injection (5 ng, 50 ng, 0.5 microg, 1.25 microg, 2.5 microg, or 5 microg). All animals developed local tetanus in the injected limb at a dose of at least 0.5 microg. The severity and duration of local tetanus was generally related to dose, but was more variable in the actively vaccinated group than in the naive or passively immunized animals. Response to the toxin over the first few days was predictive of both the duration and maximal severity of the motor response. Although vaccination dramatically increases resistance to tetanus toxin, by virtue of its extremely high potency, the toxin can produce prolonged localized tetanus even in vaccinated animals with relatively small amounts of protein. These results suggest the possible use of tetanus toxin to enhance local motor activity in a variety of neurologic conditions even in immunized humans. This study in uniformly vaccinated animals also illustrates the potential difficulties in determining an appropriate dose of toxin in a human population with variable degrees of immunity.