NZB x NZW F1 hybrid (B/W) mice develop altered behavior in the elevated plus maze and novel object tasks between 6 and 12 weeks of age in parallel with lupus-like autoimmune disease. To confirm the relationship between disease progression and development of behavioral abnormalities, B/W and nonautoimmune NZW mice received chronic treatment with a soluble IFN gamma receptor (sIFN gamma R), a treatment known to retard autoimmune disease progression, or vehicle, beginning at 6 weeks of age. After 6 weeks of treatment, elevated plus maze and novel object testing revealed that although sIFN gamma R treated B/W mice still differed from NZW mice, chronic sIFN gamma R treatment significantly retarded the development of behavioral abnormalities in the B/W mice, while the NZW mice were not affected by this treatment. sIFN gamma R treated B/W mice were more active in both the plus maze and novel object tasks, and displayed less plus maze anxiety behavior and more exploratory activity in the novel object task compared to vehicle treated B/W mice. To clarify the role of acute action of the sIFN gamma R on the elevated IFN gamma levels of B/W mice, a second experiment examined the effects of a single injection of sIFN gamma R on B/W and NZW mice. Unlike chronic treatment, acute treatment with the same dose of sIFN gamma R did not affect plus maze or novel object behavior in 12-week-old mice. These results add to the growing evidence that lupus-associated behavioral abnormalities are a direct effect of the autoimmune disease.