NZB/NZW F1 (B/W) mice have high levels of natural killing (NK), are resistant to the induction of tolerance to bovine gamma globulin (BGG), and spontaneously develop a disease resembling systemic lupus erythematosus. In vivo administration of 89Strontium (89Sr) to B/W mice reduces NK and improves their autoimmune disease. We tested the hypothesis that the high levels of NK exert an immunoregulatory influence and are responsible for the resistance to BGG tolerance. 89Sr was administered at 4 and 8 weeks, and tolerogen was injected at 10 weeks. Despite a marked suppression of NK, 89Sr-treated B/W mice remained resistant to the induction of tolerance. NK was stimulated in weanling B/W male and female mice, and in adult A/J females, by the injection of Poly I . C one day prior to the administration of tolerogen. Poly I . C induced an acute rise in NK but did not inhibit the induction of tolerance. We conclude that natural killer cells are not involved in the regulation of immune tolerance to BGG and, they do not appear to play a role in the resistance to tolerance in adult B/W mice.