The specific roles of estrogen receptor (ER) subtypes alpha and beta in mediating estrogen's influences on lupus autoimmunity are unknown. Herein we found that ovariectomized NZB/NZW F1 mice treated with propyl pyrazole triol (ERalpha-selective agonist) had significantly shorter survival, earlier development of albuminuria, higher serum concentrations of total IgG and prolactin, increased serum levels of anti-DNA IgG3, IgG2a and IgG2b and decreased anti-DNA IgG1 level compared to vehicle controls. In contrast, diarylpropionitrile (ERbeta-selective agonist) administration significantly decreased serum anti-DNA IgG2b level but did not significantly affect serum levels of other anti-DNA IgG subclasses, serum total IgG or prolactin concentration, mortality or the occurrence of albuminuria. These findings suggest that ERalpha activation plays the predominant and immunostimulatory role in estrogen-mediated modulation of lupus while ERbeta activation appears to have a slightly immunosuppressive effect on this disease. ERalpha activation coincidentally increased serum prolactin concentrations and may accelerate lupus disease activity also through this mechanism.