We describe the synchronous presentation of hepatoid adenocarcinoma of the lung and colorectal adenocarcinoma in a patient with elevated alpha-fetoprotein (AFP) serum levels. Our patient was treated after surgery with a conventional chemotherapy regimen including bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, which was demonstrated to improve the clinical results in the treatment of colorectal and lung cancer compared with chemotherapy alone, and is today approved both for colon and lung cancer. Besides the unconventional association of the two cancer types in our patient and the unsatisfactory clinical benefit obtained with the medical treatment administered, we report on the significance of AFP serum levels as a tumor marker in this peculiar situation. In our patient these levels, monitored from the first clinical symptoms through the last chemotherapy course, did not show any correlation with the response to treatment or with the patient's overall outcome. In particular, the serum marker remained essentially unchanged after the surgical removal of the lung mass and the subsequent chemotherapy.