Contemporary chemotherapy is limited by disseminated, resistant cancer. Targeting nanoparticulate drug delivery systems that encapsulate synergistic drug combinations are a rational means to increase the therapeutic index of chemotherapeutics. A lipopolymeric micelle co-encapsulating an in vitro optimized, synergistic fixed-ratio combination of paclitaxel (PTX) and clofazimine (B663) has been developed and called Riminocelles™. The present pre-clinical study investigated the acute toxicity, systemic exposure, repeat dose toxicity and efficacy of Riminocelles in parallel to Taxol® at an equivalent PTX dose of 10 mg/kg. Daily and weekly dosing schedules were evaluated against Pgp-expressing human colon adenocarcinoma (HCT-15) xenografts implanted subcutaneously in athymic mice. Riminocelles produced statistically significant (p < .05) tumor growth delays of 3.2 and 2.7 days for the respective schedules in contrast to Taxol delaying growth by 0.5 and 0.6 days. Using the control tumor doubling time of 4.2 days, tumor-cell-kill values of 0.23 for Riminocelles and 0.04 for Taxol following daily schedules were calculated. A significant weight loss of 5.7% after 14 days (p < 0.05) relative to the control group (n = 8) was observed for the daily Taxol group whereas Riminocelles did not incur significant weight loss neither were blood markers of toxicity elevated after acute administration (n = 3). The safety and efficacy of Riminocelles is statistically superior to Taxol. However, passive tumor targeting was not achieved and the tumor burden progressed quickly. Prior to further animal studies, the in vivo thermodynamic instability of the simple lipopolymeric micellular delivery system requires improvement so as to maintain and selectively deliver the fixed-ratio drug combination.