Serum is the blood component that is obtained after coagulation and removal of cellular components. Besides serum proteins, it contains, e.g. growth factors, amino acids, and hormones. This complex mixture makes serum one of the most important supplements supporting the cells growth and proliferation for in vitro cell culture. Of special interest is the Fetal Bovine Serum (FBS). It is especially rich in growth factors and is particularly low in antibodies that may negatively influence the cell culture work. It supports most cell lines and undergoes strict quality controls. Fetal Bovine Serum contains a naturally huge amount of exosomes, carrying the potential risk of interference with exosomes secreted by the cells – a highly critical problem in exosome research. Our newly developed method to eliminate exosomes is efficient but gentle to other FBS components. In comparison with non-depleted FBS, the cell culture performance is still outstanding.