The subcutaneous implantable cardioverter defibrillator (S-ICD) has been established as a valuable alternative to transvenous ICD for prevention of sudden cardiac death. The system automatically chooses the optimal sensing vector. However, during follow-up and especially after device replacement we observed a change of the suggested sensing vector in automatic setup. Therefore, we analyzed frequency and reasons of vector change and its impact on inappropriate shocks (IAS). Between June 2010 and December 2017, a total of 216 patients with S-ICD® were included in this analysis. In all patients sensing vectors at the time of implantation, during follow-up, and after device replacement were investigated. Median follow-up time was 27.3 ± 25.3 months. A change of the initial vector was seen in 77 patients (35.7%). The most frequent reason for vector change was the postoperative setup in supine and erect position in 54 patients (70.1%). In 12 patients (15.5%), the vector was manually changed due to inappropriate sensing and/or therapies. Routine setup during follow-up led to automatic vector change in 10 cases (13.0%). In only 1 patient the vector was manually changed due to oversensing in an exercise treadmill test. In 27 patients, the device was replaced due to battery depletion and in 6 of these patients the sensing vector was changed by the automatic setup. Vector change did not have an impact for inappropriate therapies in the follow-up; only 1 patient received an IAS due to an inadvertent vector change after device replacement. In the present study, a significant number of S-ICD® patients had a manual or automatic vector change during follow-up and after device replacement. The study underlines the importance of a thoroughly performed screening and at least two valuable sensing vectors preimplant. Further studies are needed to evaluate the necessity of a routine automatic setup during follow-up.