The efficacy of bevacizumab combined with infusional 5-fluorouracil/leucovorin (5-FU/LV) plus irinotecan (FOLFIRI) as the second-line treatment for metastatic colorectal cancer (mCRC) has not been fully clarified, although bevacizumab combined with infusional 5-FU/LV plus oxaliplatin (FOLFOX) in the second-line setting has demonstrated a survival benefit. We investigated the efficacy of bevacizumab plus FOLFIRI in mCRC patients who failed oxaliplatin-containing regimens without bevacizumab. Patients who received bevacizumab plus FOLFIRI or bevacizumab plus FOLFOX as second-line chemotherapy between July 2007 and March 2008 were registered (trial registration: UMIN000001547). Patient background data and progression-free survival (PFS), overall survival (OS), response, and bevacizumab-related adverse events were prospectively collected every 6 months. A total of 195 patients were enrolled from 26 institutions. Among them, 115 patients received bevacizumab plus FOLFIRI after failure of oxaliplatin and fluoropyrimidine (FOLFIRI+BV after OX/FU group), and 45 patients received bevacizumab plus FOLFOX after failure of irinotecan and fluoropyrimidine (FOLFOX+BV after IRI/FU group). Median PFS was 8.3 months (95% confidence interval [CI], 6.7-9.9) for the FOLFIRI+BV after OX/FU group and 7.8 months (95% CI, 5.8-9.7) for the FOLFOX+BV after IRI/FU group. Median OS was 21.6 months (95% CI, 17.6-25.6) and 16.5 months (95% CI, 11.8-21.2), respectively. Overall response rates were 25 and 29%, respectively. The most common grade≥3 bevacizumab-related adverse events were hypertension (5.0%) and bleeding (3.8%). FOLFIRI+BV after OX/FU showed comparable efficacy to FOLFOX+BV after IRI/FU.