In the literature, many papers deal with the behavior of proteins in aqueou
s media in the presence of poly(ethylene glycol) (PEG) molecules or poly(et
hylene oxide) (PEO) segments, physically adsorbed onto, or covalently attac
hed to, macromolecules or to solid surfaces. In particular, it is well know
n that PEO segments make foreign materials stealthy, i.e. they are much les
s detected by the immune system either through humoral reactions or, at the
cell level, through opsonins. Revisiting the literature led us to challeng
e the largely accepted opinion that the decreased recognition of PEO segmen
t-bearing foreign macromolecules and particles by the mononuclear phagocyte
system is primarily the consequence of the repulsion of all blood proteins
by PEG segments through the excluded volume effect. This challenge is base
d on the finding that albumin and PEG are compatible in phosphate-buffered
saline at room temperature and at concentrations comparable to those measur
ed by others on the surface of PEO segment-bearing species, whereas fibrino
gen and PEG phase-separated and were incompatible despite the much lower co
ncentration of the latter protein. According to literature and to these obs
ervations, it is proposed that the stealth effect induced by PEO segments i
s primarily due to the compatibility between PEO segments of intermediate m
olar mass and albumin, thus rendering PEG-bearing macromolecules or surface
s to look like native albumin. Under such conditions, the hospitality offen
d by PEG macromolecules or PEO segments to albumin, the dominant plasma pro
tein, results in a 'chameleon' effect that prevents the activation of other
PEG-compatible or -incompatible plasma proteins or cells involved in forei
gn body recognition and elimination. PEG with molar masses greater than or
equal to 8000 did not accommodate albumin in agreement with the excluded vo
lume phenomenon.