Extensive evidence supports a role for natural antibody (NAb) acting against small tumour foci in vivo. Ras-transformation of murine C3H 10T½ fibroblasts, known to partially activate and down-regulate endogenous PKC-α, increased their serum NAb-binding capacity consistent with the requirements for natural immune surveillance. Now a rat PKC-β1-overexpressing 10T½ clone, PKC-4, with an 11-fold increase in PKC activity and an activated, partially transformed phenotype, links higher susceptibility to transformation through v-Haras infection with an 80% increase in NAb binding assayed by flow cytometry. H7 and E-64d inhibition and phorbol ester depletion of PKC reduced NAb binding. PKC-β1 expression and NAb binding exhibited a similar temporal recovery from TPA treatment. Thus, expression of NAb-binding structures appears to be elevated by constitutive increases in the basal activation of PKC in both the ras-transformation and the PKC-β1-preneoplasia models. This, coupled with corresponding decreases in membrane PKC-α and NAb binding in confluent 10T½ cells raises the possibility that in general, cells activated through PKC are NAb sensitive. Together with the increased in vivo elimination of the high NAb-binding PKC-4 cells, the data extend the support for a role for NAb in immune surveillance, to resistance against preneoplastic cells, and argue for NAb contributing to homeostasis of the organism.