Resection of infiltrated tumor-draining lymph nodes (TDLNs) is a standard practice for the treatment of several cancers including breast cancer and melanoma. However, many randomized prospective trials have failed to show convincing clinical benefits associated with LN removal and the role of TDLNs in cancer dissemination is poorly understood. Here, we found in a well-characterized spontaneous mouse model of uveal melanoma that the growth of the primary tumor was accompanied by increased lymphangiogenesis and cancer cell colonization in the LNs draining the eyes. But, unexpectedly, early resection of the TDLNs increased the growth of the primary tumor and associated blood vessels as well as promoted cancer cell survival and dissemination. These effects were accompanied by increased tumor cell proliferation and expression of phosphorylated AKT. Topical application of a broad anti-inflammatory agent, Tobradex, or an oral treatment with cyclooxygenase-2 specific inhibitor, Celecoxib, reversed tumor progression observed after complete lymphadenectomy. Our study confirms the importance of tumor homeostasis in cancer progression by showing the enhancing effects of TDLN removal on tumor growth and cancer cell dissemination, and suggests that TDLN resection may only be beneficial if used in combination with anti-inflammatory drugs such as Tobradex and Celecoxib.