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Abstract: It has been well established that there is a decline in immune function with age resulting in a diminished capacity to respond to infections or tumors. Although many studies have demonstrated the efficacy of autologous dendritic cells (DC) vaccines in stimulating an anti-tumor immune response in the young, almost none of these reports consider the effect that aging has on the immune system or test whether DC-vaccination is effective in old hosts. In this study we compared the efficacy of DC-vaccination in young and old mice. Our results showed that DC-vaccination in young animals induced an anti-tumor response resulting in ∼60% tumor growth inhibition, while minimal protection was observed in old animals. DC vaccination plus rIL-2 further enhanced the anti-tumor response in young animals (∼70–75% inhibition), while ineffective in old animals. In contrast, co-administration of anti-OX-40 or anti-4-1BB mAbs vigorously enhanced the anti-tumor immune response in both young (∼85–90% inhibition) and old mice (∼70–75% inhibition). Our data indicate that although old mice have a decline in immune function, they have the capacity to develop strong anti-tumor responses as long as they are provided with efficient co-stimulation. [Copyright &y& Elsevier]