We examined the therapeutic efficacy of xenogenic human N'-terminal neu DNA vaccine and autologous mouse N'-terminal neu DNA vaccine on MBT-2 tumor cells in C3H mice. Intramuscular injection of xenogenic and autologous neu DNA vaccines produced comparable therapeutic efficacies. Mouse and human N'-neu DNA vaccine induced tumor infiltration of CD8(+) T cells, while the human vaccine was less effective at stimulating natural killer cells. Depletion of CD8(+) T cells abolished the therapeutic efficacy of both types of DNA vaccines. On the other hand, xenogenic neu DNA vaccine showed significantly better therapeutic efficacy than autologous DNA vaccine with gene gun immunization. Increased infiltration of CD8(+) T cells was correlated with enhanced therapeutic efficacy in the human N'-neu group of mice. Therefore, intramuscular injection can enhance the therapeutic efficacy of autologous neu DNA vaccine.