An antibody population which reacts only with human sickle cell hemoglobin (HbS) and not with normal human hemoglobin, has been isolated from goat, sheep, and guinea pig antisera. These antibody populations termed anti-Val (Val), isolated from an individual goat (no. 6) and sheep (no. 26) have been used to elicit anti-idiotypic responses in rabbits. These anti-idiotypic sera were used to study the idiotypic cross-reactions between the goat and sheep anti-Val. Strong cross-reactions were present using either Ra anti-goat anti-Val or Ra anti-sheep anti-Val. Guinea pig anti-Val did not cross-react with these anti-idiotypic sera. Binding of HbS to the anti-Val of the goat and sheep could be blocked by the anti-idiotypic sera, but the binding of HbS to the guinea pig anti-Val could not. These data demonstrate idiotypic cross-reactivity between two closely related species.