Paclitaxel is a chemotherapeutic agent used for the treatment of metastatic breast cancer. 2,5,7,8-Tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid (alpha-TEA) is an analog of vitamin E that inhibits primary tumor growth and the incidence of lymphatic and pulmonary metastases in preclinical animal models. Here, the efficacy of sequential treatment with paclitaxel and alpha-TEA was tested in the BALB/c syngeneic 66cl-4-GFP mammary cancer model. Both agents were formulated into liposomes and delivered by inhalation in an effort to increase anti-tumor efficacy and minimize paclitaxel toxicity. Combination treatment consisting of twelve days of every-other-day treatment with aerosolized paclitaxel (approximately 0.46 microg/mouse/treatment) followed by a daily regimen of aerosolized alpha-TEA (36 microg/mouse/treatment) significantly decreased primary tumor burden when compared to untreated or liposome control groups and was significantly better than individual treatments (P < 0.05). Importantly, combination treatment was significantly better at reducing lung and lymph node micrometastatic foci when compared to control and individual treatment groups (P < 0.05). Immunohistochemical analyses of tumor sections showed combination treatment when compared to liposome control or individual treatments to significantly decrease total number of cells staining positive for the endothelial cell marker CD31 or for the Ki67 marker of cellular proliferation and increase the number of apoptotic (TUNEL positive) tumor cells (P < 0.001). Studies addressing the toxicity of alpha-TEA demonstrated that alpha-TEA formulated in liposomes and delivered by aerosol (72 microg/mouse/day) or gavage (5 mg/mouse/day) for 25 days did not cause blood, liver, or kidney toxicity. In conclusion, sequential inhalation delivery of liposomal-formulated paclitaxel and alpha-TEA produces significantly better anti-tumor outcomes than single treatments.