For advanced colorectal carcinoma, two new drugs, raltitrexed (TOM) and oxaliplatin (L-OHP), have recently shown interesting results. Preclinical and clinical studies suggest that this combination, because of its favorable toxicity profile, high response rate and convenient schedule of administration, can be administered successfully in this disease. In our phase II study, 37 non pre-treated patients with metastatic colorectal carcinoma were treated with TOM (3 mg/m2) and L-OHP (130 mg/m2) every 3 weeks. In total, 222 cycles were administered; all patients received at least 2 cycles (median 6, range 2–8). There were two complete and 14 partial responses for an overall response rate of 43% (95% CI 27–69%). The median time to response was 2.5 months (range 2–4) and the median duration was 10.3 months (range 5–18). Twelve of the 23 (52%) patients with symptomatic colorectal cancer were classified as clinical benefit responders for at least 4 weeks during the study period. Treatment was well tolerated, and both acute, essentially hematologic, and cumulative hepatic and neurologic toxicities were manageable and reversible. Response rate and toxic effects observed during this study warrant additional studies comparing this TOM–L-OHP regimen with CPT-11 and/or capacitebine-containing regimens in metastatic colorectal carcinoma.