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Background In response to the national leucovorin shortage in 2008, our institution adjusted the modified FOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) protocol to utilize a lower dose of leucovorin (20 mg/m2). This adjustment was based on prospective studies suggesting that lower doses of leucovorin may be equally effective in other fluorouracil containing regimens. This retrospective study evaluates outcomes in metastatic colorectal cancer (mCRC) patients treated with low- (20 mg/m2) vs. high-dose (400 mg/m2) leucovorin in the FOLFOX6 regimen for mCRC. Methods This retrospective analysis included consecutive mCRC patients from 2004 to 2011 if they received at least one cycle of modified FOLFOX6 as first line therapy. Patients who received an initial leucovorin dose other than 20 mg/m2 or 400 mg/m2 on their first cycle were excluded. Patient characteristics included demographics, metastatic site at initial diagnosis, and treatment history including chemotherapy and surgery. Primary outcome was date of death or last contact. Cox proportional hazards regression analysis and Kaplan–Meier survival curves were utilized to evaluate the effect of leucovorin dose on overall survival. Log-rank tests were used to compare median survival times by dose group. Results Of the 93 mCRC patients who received first line modified FOLFOX6, leucovorin 400 mg/m2 was administered to 47 (51%) patients and 20 mg/m2 to 46 (49%) patients. There were no differences of baseline characteristics between the groups with exception of primary site of cancer (p = 0.038). The overall survival time was 22.5 months (95% CI 16.6–29.6). The median survival time in the leucovorin 400 mg/m2 group was 23.1 months (95% CI 16.2–35.7) compared to leucovorin 20 mg/m2 which was 20.5 months (95% CI 14.2–34.2); p = 0.573. The median survival times in patients with one versus two or more sites with metastasis were statistically different (26.9 vs. 16.2 months, p = 0.009). Metastatic site removal or ablation showed differences in the median survival, 34.2 months (95% CI 20.8–50.9) vs. 16.6 months (95% CI 14.1–23.6) without metastatic disease removal (p = 0.004). The odds of dying for patients with two metastatic sites was higher compared with the odds of those patients with one site, HR 1.8 (95% CI 1.08–3.0). Patients without metastatic site removal or ablation had higher odds of dying compared to those patients without this procedure, HR 0.47 (95% CI 0.27–0.81). Conclusion In this single center retrospective study, there was no difference in overall survival for mCRC patients treated with first line FOLFOX6 with low- vs. high-dose leucovorin. [ABSTRACT FROM AUTHOR]