Recent studies suggest that tumor-infiltrating immune cells can benefit the tumor by producing factors that promote angiogenesis and suppress immunity. Because the tumor microenvironment is characterized by high adenosine levels, we hypothesized that the low-affinity A_2B adenosine receptor located on host immune cells may participate in these effects. In the current study, we tested this hypothesis in a Lewis lung carcinoma isograft model using A_2B receptor knockout (A_2BKO) mice. These mice exhibited significantly attenuated tumor growth and longer survival times after inoculation with Lewis lung carcinoma compared to wild type (WT) controls. Lewis lung carcinoma tumors in A_2BKO mice contained significantly lower levels of vascular endothelial growth factor (VEGF) compared to tumors growing in WT animals. This difference was due to VEGF production by host cells, which comprised 30 ± 2% of total tumor cell population. Stimulation of adenosine receptors on WT tumorinfiltrating CD45⁺ immune cells increased VEGF production fivefold, an effect not seen in tumor-associated CD45⁺ immune cells lacking A_2B receptors. In contrast, we found no significant difference in VEGF production between CD45⁻ tumor cells isolated from WT and A_2BKO mice. Thus, our data suggest that tumor cells promote their growth by exploiting A_2B adenosine receptor–dependent regulation of VEGF in host immune cells.