Background: PTL is a prognostic factor for mCRC. Recent data suggest PTL is also predictive of survival benefit with cetuximab (CET) and bevacizumab (BEV). This study evaluated the prognostic and predictive effect of PTL in patients with KRAS WT mCRC who initiated first-line (1L) therapy with CET vs BEV in the real world. Methods: This retrospective study selected patients with KRAS WT mCRC who initiated 1L therapy with CET or BEV + FOLFIRI or FOLFOX between January 2013 and April 2017 from Flatiron Health’s electronic health record-derived database. PTL was abstracted from patients’ charts. Left-sided PTL (LPTL): splenic flexure to rectum; right-sided PTL (RPTL): cecum to splenic flexure. Propensity score matching was used to balance treatment cohorts on baseline characteristics. Kaplan Meier and Cox regression methods were used for survival analyses. Results: 1,312 patients met the selection criteria. Of 248 CET + FOLFIRI or FOLFOX patients, 164 had LPTL and 84 had RPTL; of 1,064 BEV + FOLFIRI or FOLFOX patients, 679 had LPTL and 385 had RPTL. CET LPTL and RPTL patients were more likely to receive FOLFIRI vs BEV patients (LPTL: 64.0% vs 24.3%; P<.001; RPTL: 76.2% vs 24.9%; P<.001). Stage at initial diagnosis was different between CET RPTL vs BEV RPTL patients (P<.001). CET RPTL patients were more likely to be stage III (44.0% vs 22.6%) while BEV RPTL patients were more likely to be stage IV (48.8% vs 65.7%) at initial diagnosis. CET RPTL patients were more likely to have a history of adjuvant chemotherapy vs BEV RPTL patients (47.6% vs 22.3%; P<.001). In the matched sample, median overall survival (OS) was 29.7 months (95% CI, 26.9–35.2) for LPTL patients vs 18.3 months (95% CI, 15.8–21.3) for RPTL patients (P<.001). Median OS was 29.7 months (95% CI, 27.4–NA) for CET LPTL vs 29.1 months (95% CI, 26.6–35.6) for BEV LPTL patients (HR, 0.87; 95% CI, 0.63–1.19; P=.378), and 17.0 months (95% CI, 12.0–32.6) for CET RPTL vs 18.8 months (95% CI, 15.8–22.3) for BEV RPTL patients (HR, 1.00; 95% CI, 0.68–1.46; P=.996). The interaction of treatment and PTL was not significant in the Cox regression. Conclusions: This study found a prognostic effect of PTL but not a predictive effect. LPTL patients had significantly longer OS vs RPTL patients. However, the treatment effect for CET vs BEV by PTL was not significantly different. Future research is needed to examine differences between real-world and clinical trial populations that may have contributed to divergent results.