Background: Systemic chemotherapy with a 5-FU-based regimen, such as mFOLFOX6, is the preferred first line treatment option for mCRC. Due to hematologic toxicities associated with the 5-FU bolus component, providers may choose to eliminate it empirically in patients receiving palliative therapy. This study aimed to assess the impact of empirically eliminating the 5-FU bolus and LV from first line treatment with mFOLFOX6 in mCRC. Methods: This was a retrospective chart review of patients ≥ 18 years old with mCRC receiving palliative first line mFOLFOX6 chemotherapy with (bolus) or without (non-bolus) the 5-FU bolus and LV components from January 1, 2015 through August 31, 2019 at Moffitt Cancer Center. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR) defined as partial response and stable disease at first scan, utilization of growth factor support and safety. Results: Data analysis cutoff was December 31, 2019, with 61 patients included in the bolus arm and 72 in the non-bolus arm. Median follow-up time was 21.8 months. No difference was found in median PFS (8.12 vs. 6.64 months, p=0.787) or OS (29.36 vs. 21.6 months, p=0.395) between the bolus and non-bolus arms, respectively. Observed DCR at first scan was similar between both arms (47.3% vs. 52.7%, p=0.44). Utilization of growth factor support was significantly higher in the bolus arm (73.7% vs. 26.3%, p=0.012). Fewer grade ≥ 3 treatment-related hematologic adverse events (AE) were seen in the non-bolus arm (37.7% vs. 22.2%, p=0.058) (table). Conclusions: This is the only study to date that analyzed the impact of empirically eliminating 5-FU bolus and LV from first line palliative therapy with mFOLFOX6 in mCRC. Results showed no significant difference in median PFS or OS. Despite reduced growth factor utilization, the non-bolus arm demonstrated a favorable safety profile with less treatment-related hematologic grade ≥ 3 AE. The results of this study warrant consideration of empirically eliminating 5-FU bolus and LV from the mFOLFOX6 regimen to avoid additive toxicities without negatively impacting efficacy.