Dendritic cells are potent antigen-presenting cells that have been shown to have significant antitumor effects in vitro and in vivo. However, the therapeutic efficacy of dendritic cells as an immunotherapeutic treatment has been limited by both immunologic tolerance and active immunosuppression in the tumor microenvironment. To address this problem, we examined the ability of concurrent systemic chemotherapy and local, fractionated radiation to augment intratumoral dendritic cell injections in a mouse model of squamous cell carcinoma. Intratumoral injections of dendritic cells alone did not have a significant antitumor effect in mice with squamous cell carcinoma flank tumors, but the addition of chemoradiation resulted in significant tumor regression. Concurrent chemoradiation alone resulted in slower tumor growth, but no complete tumor regressions. The combination of chemoradiation and intratumoral dendritic cell injections resulted in improved survival and complete tumor regression in 30% mice. Mice with complete tumor regression were partially resistant to the repeat challenge with relevant tumor 60 days after treatment. These findings were partially dependent on the presence of CD4 T cells, CD8 T cells, and natural killer cells. Chemoradiation may augment intratumoral dendritic cell injections through increased intratumoral apoptosis and decreased intratumoral regulatory T cells. This work suggests a possible role for the use of intratumoral dendritic cell therapy with more traditional chemoradiation strategies.