Colon cancer patients with severe hepatic dysfunction secondary to liver metastases have limited treatment options. 5-Fluorouracil (5-FU) infusional therapy has been attempted, but data suggesting significant clinical benefit are lacking. Although both 5-FU and oxaliplatin have been well tolerated as single agents in patients with severe hepatic dysfunction, the combination of these drugs in this setting has not been investigated. We report on three patients with severe liver dysfunction secondary to metastatic colon cancer treated with a combination of 5-FU, oxaliplatin, and leucovorin (FOLFOX). All three patients tolerated chemotherapy well without any significant toxicity. Liver function tests improved within 2 weeks from the start of treatment. Clinical outcomes consisted of two partial responses and one disease stabilization. Two patients progressed after 4 and 7 months from FOLFOX initiation while treatment is ongoing in the third patient. FOLFOX chemotherapy is feasible and can be associated with positive outcomes in patients with metastatic colon cancer and severe hepatic dysfunction. This regimen should be investigated further in similar clinical settings.