The pituitary hormone, prolactin, accelerates systemic lupus erythematosus in NZB/NZW F1 (B/W) mice. Our study evaluated disease activity in B/W females experiencing the physiologic hyperprolactinemia of mating, pregnancy, suckling, and pseudopregnancy. Nonsuckling postpartum, suckling and pseudopregnant mice were compared to virgin females. Serum prolactin, anti-DNA antibodies (anti-DNA), gp70-anti-gp70 immune complexes, IgM, IgG, albuminuria, and renal function were monitored serially. Females that whelped 2 litters had apparent stimulation of anti-DNA; those that suckled their young had similar premature appearance of anti-DNA as well as delayed, but marked, hypergammaglobulinemia. Pseudopregnant mice, which characteristically secrete repeated surges of prolactin, had significant acceleration of multiple variables of disease activity. Pregnancy, parturition and suckling did not immediately accelerate lupus in B/W dams, and longevity was not affected in females that had borne litters. Pseudopregnancy was the most effective stimulator of variables of autoimmunity.