ALIMTA, oxaliplatin, and 5-fluorouracil (alone or with leucovorin) have shown activity as single agents in the treatment of colorectal cancer. Their different mechanisms of action make the combination of ALIMTA with oxaliplatin attractive as potential first-line therapies in terms of improving response rates and overall survival in patients with metastatic colorectal cancer. Current reports of the combination of oxaliplatin and 5-FU as first-line therapies suggest that there may be advantages in combining oxaliplatin with other antifolates in the treatment of colorectal cancer. ALIMTA is an attractive candidate to replace other drugs such as 5-FU in the combinations with oxaliplatin in the treatment of locally advanced and metastatic colorectal cancer. ALIMTA has potential advantages over 5-FU when combined with oxaliplatin because it requires a single short injection and inhibits multiple targets in the folate pathway. Therefore, we propose to conduct a trial reporting the clinical effectiveness and side effects of ALIMTA plus oxaliplatin and one of the current standards of care, the FOLFOX 4 regimen (Oxaliplatin plus 5-Fluorouracil and Leucovorin).