Many retroviral vectors for hematopoietic cell and other clinical gene therapy are derived from murine packaging cell lines. The exposure of these retroviruses and packaging cell lines to adult human serum (AS) inactivates them by complement and anti-alpha-galactosyl natural antibody-mediated mechanisms. We show that virus stability and infection efficiency of CRIP/BAG, a murine packaging cell line derived amphotropic retrovirus vector is reduced > 95% following a 30-min incubation in AS. This inactivation is prevented by replacing AS with umbilical cord serum (CS), wherein full retroviral transduction efficiency is maintained after 30 min of incubation. The loss of retrovirus transduction efficiency in AS was smaller upon blockage of anti-alpha-galactosyl antibodies with galactose alpha 1-3-galactose. Serum levels of CH 100, as well as C1q complement which inactivates retroviruses by an antibody-independent mechanism were similar in AS and CS. The high stability of CRIP/BAG retrovirus vector in CS is likely due to its lower levels of maternally derived anti-alpha-galactosyl antibodies. These results have implications for in vivo gene transfer in adults and also in newborns since neonates do not produce natural antibodies during the initial months of life.