Ascites related to metastatic colorectal cancer (mCRC) reduces patient survival and quality of life, and systemic chemotherapy is largely ineffective for managing ascites. Here, we examined the clinical efficacy of intraperitoneal (IP) ziv-aflibercept for managing refractory ascites in 15 mCRC patients who did not respond to standard chemotherapy. Fifty or 100 mg of ziv-aflibercept in 100 mL of saline solution were infused through a pigtail catheter and retained for 24 h. When the ascites drainage volumes were subsequently monitored, 73.3% of patients showed an objective response (OR) to IP ziv-aflibercept treatment. Patients with low Eastern Cooperative Oncology Group (ECOG) performance status or with serum ascites albumin gradients (SAAG) less than 1.1 g/dL had better responses to treatment, and 4 patients with SAAG less than 1.1 g/dL showed rapid objective responses (rOR). These findings indicate that intraperitoneal ziv-aflibercept therapy may be a highly effective means of treating refractory ascites in mCRC patients, and that SAAG may be predictive of a rapid response to this treatment.