Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and lower side effects, especially in combination with other antiangiogenic agents. This study aims to investigate whether LDM chemotherapy of paclitaxel could synergize with cetuximab, an antiangiogenic agent to suppress HT-29 human colon tumors in BALB/c nude mice. To explore its possible mechanism, the tumor vascular status was detected by staining with anti-CD31 Ab and the tumoral expression of thrombospondin-1 was examined by immunohistochemistry, western blot analysis, and real-time PCR. Our results showed that empirical metronomic paclitaxel regimens in combination with cetuximab induces significant and durable antitumor responses without overt toxicity. Paclitaxel LDM chemotherapy displayed stronger antiangiogenic activity than maximum tolerable dose (MTD) chemotherapy, whereas MTD chemotherapy induced more apoptotic cells. The combinational therapy with LDM and cetuximab showed the strongest antiangiogenic activity among all the groups. Paclitaxel LDM chemotherapy also dramatically upregulated the expression of thrombospondin-1, but MTD chemotherapy did not. These results suggest that the combination of paclitaxel LDM chemotherapy and cetuximab represents a potent strategy to combat colon cancers.