BACKGROUND: Second as well as higher-line therapies have a significant influence on progression-free and overall survival of metastatic colorectal cancer patients. However, treatment of late-stage disease remains suboptimal. Therefore, the introduction of new, effective and well-tolerated agents is of major importance. Case Reports: Here we describe the cases of 2 patients with metastatic KRAS wild-type colorectal cancer who received a fourth-line monotherapy with panitumumab after failure of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab. RESULTS: Both patients achieved a partial remission, and for 11.5 and 18 months, respectively, they had a stable disease with initial reduction in the tumor marker carcinoembryonic antigen. Both patients reported a good tolerability of the treatment with improved quality of life (compared to receiving combined chemotherapy). CONCLUSION: Panitumumab monotherapy is an effective and well tolerated treatment of metastatic colorectal cancer in extensively pretreated KRAS wild-type patients. Our data have shown a response to panitumumab monotherapy for more than 11 months.