Rationale: Aminobiphosphonates, such as zoledronic acid (ZA), exert potent indirect anti-tumor effects and are currently tested against human solid tumors. The anti-tumor actions of aminobiphosphonates, including angiostasis, are relevant to the pathogenesis of malignant pleural effusion (MPE), but no study has addressed the efficacy of these compounds against malignant pleural disease. Objectives: Here we hypothesized that treatment of immunocompetent mice with ZA would halt tumor progression in a mouse model of adenocarcinoma-induced MPE. Methods: To induce MPE in mice, Lewis lung carcinoma (LLC) cells were delivered directly into the pleural space. Subsequently, animals were treated with ZA in both a prevention and a regression protocol. Measurements and Main Results: ZA treatment resulted in significant reductions in pleural fluid accumulation and tumor dissemination, while it significantly prolonged survival. These effects of ZA were linked to enhanced apoptosis of pleural tumor cells, decreased formation of new vessels in pleural tumors, and reduced pleural vascular permeability. In addition, ZA was able to inhibit the recruitment of mononuclear cells to pleural tumors, with concomitant reductions in matrix metalloproteinase (MMP)-9 release into the pleural space. Finally, ZA limited the expression of proinflammatory and angiogenic mediators, as well as the activity of small GTP-proteins Ras and RhoA, in tumor cells in vivo and in vitro. Conclusions: ZA is effective against experimental MPE, suggesting that this intervention should be considered for testing in clinical trials.