The best second-line therapy in patients with wild-type KRAS metastatic colorectal cancer was investigated in terms of drug choice, duration of therapy, and efficacy of subsequent therapy in patients treated with first-line FOLFIRI plus either cetuximab (arm A) or bevacizumab (arm B) in the FIRE-3 trial. Second-line therapy was given for a median of 5.0 months for patients in arm A versus 3.2 months for those in arm B. Both overall and progression-free survival after initiation of second-line treatment were longer in patients in arm A than those in arm B. In this patient population, first-line anti-EGFR therapy might enable more-effective subsequent treatment, including responses to antiangiogenic agents.