The superior vena cava syndrome is due to the increased venous pressure in the upper torso, neck and head, caused by the obstruction of the superior vena cava. Both external and internal factors cause obstruction (95% are malign causes), and the most severe manifestation is represented by cerebral edema that can even lead to coma. The diagnostic algorithm for the superior vena cava syndrome is widely known. There are many controversies and discussions about the safety of histopathological sampling. The purpose of this paper is to assess such risks, the complication rate and the diagnostic yield of surgical sampling, by analyzing the 26 interventions performed in our clinic. Although the complication rate was higher than that observed in the absence of the superior vena cava syndrome, surgery remains mandatory for a rapid histopathological diagnosis, therefore demanding a protocol that must include a mandatory extemporaneous exam of the biopsy.