Most cancers emerge in the elderly, including lung cancer and mesothelioma, yet the elderly remain an underrepresented population in pre-clinical cancer studies and clinical trials. It is well established that the immune system plays a critical role in the effectiveness of many anti-cancer therapies in young hosts via tumour-specific T cells. However, immunosuppressive macrophages can constitute up to 50% tumour burden and impair anti-tumour T cell activity. It is unknown if this occurs during anti-cancer therapy in the elderly. Therefore, we examined macrophage:T cell interactions in young (3 months, equivalent to 18 years) and elderly (22-24 months, equivalent to 65-70 years) AE17 mesothelioma-bearing C57BL/6J mice treated with intra-tumoural IL-2/anti-CD40 immunotherapy. Mesothelioma tumours grew faster in elderly compared to young mice, which corresponded with an increase in tumour-associated macrophages (36.3% ± 2.1% versus 27.0% ± 2.8%). Suppressive IL-10 secreting macrophages also increased in elderly spleens and bone marrow; these sites can supply macrophages to tumours. In vitro co-culture assays with allogeneic young Balb/c T cells showed that elderly, but not young tumour-associated macrophages led to proliferation of CD4+IL-10+ Balb/c T cells. Immunotherapy was less effective in elderly (45% tumour regression) compared to young mice (100% regression) and was associated with decreased in vivo anti-tumour cytotoxic T cell activity in tumour draining lymph nodes and spleens. Interestingly, depletion of macrophages using F4/80 antibody in elderly, but not young mice, improved IL-2/anti-CD40 immunotherapy leading to 78% tumour regression. Furthermore, macrophage depletion also increased in vivo anti-tumour T cell activity in elderly, but not young mice. These studies suggest that macrophages play a critical role in sabotaging anti-tumour immune responses in the elderly.