Coumestrol is a naturally occurring plant estrogen. As estrogen influences cellular and humoral immunity, and has known effects on murine models of lupus, we investigated the effect of coumestrol on disease expression in the NZB/W F1 mouse. Female NZB/W F1 mice were fed a "standard" rodent diet including soy proteins, a non-soy diet, or a non-soy diet with 0.01% coumestrol. Outcome measures included survival, autoantibody expression, immunoglobulin levels, proteinuria, renal histology and B cell immunohistochemistry, and renal mRNA expression. At 24 weeks, the treatment group had decreased prevalence of autoantibodies detected by immunofluorescence and less splenomegaly. At 39 weeks, the prevalence of autoantibodies was similar but the treatment group had less proteinuria. Overall, there was little effect of treatment on renal mRNA levels as assessed by gene array analysis, but functional ontology mapping revealed that genes encoding proteins involved in the immune response were most often affected. These results suggest that treatment with coumestrol may ameliorate some aspects of disease progression in this model of systemic autoimmunity.