The major histocompatibility complex (MHC) is one of the genetic factors involved in the control of susceptibility to MTV-induced mammary tumors in mice. Previously, genetic differences in mammary tumor susceptibility were shown to be mainly due to differences in susceptibility of the mammary gland itself. Such experiments, however, were carried out using inbred strains which differ in many genes. Therefore, the conclusion drawn from such experiments is not necessarily applicable to every gene involved. We tested whether in the strain C57BL/10 (B10, resistant) and the H-2 congeneic strain B10.A(5R) (5R, susceptible), which differ only at the MHC, the MHC-controlled difference in tumor susceptibility indeed resides in the mammary gland tissue itself, or is caused by systemic factors. Mammary glands of infant B10 and 5R mice were transplanted into mammary fat pads of C3H-MTV-infected mammectomized (B10 X 5R)F1 females. The hosts received a hypophyseal isograft under the kidney capsule or were subjected to force-breeding to provide hormonal stimulation necessary for mammary tumor development. Control groups of C3H-MTV-infected B10, 5R and (B10 X 5R)F1 females and (B10 X 5R)F1 females without C3H-MTV were also subjected to the 2 types of hormonal stimulation. There was no difference in susceptibility between the 5R and B10 mammary glands transplanted into C3H-MTV-infected F1 hybrid hosts. On the other hand, C3H-MTV-infected 5R and (B10 X 5R)F1 females were significantly more susceptible than the C3H-MTV-infected B10 females, when either of the 2 methods of hormonal stimulation was used. This indicates that, in the strains used, MHC-controlled susceptibility to C3H-MTV-induced mammary tumorigenesis is predominantly or exclusively controlled by systemic factors rather than by factors residing in the target tissue.