It has been repeatedly shown that the heavy metal mercury can induce or exacerbate lupus like autoimmunity in susceptible strains of rats and mice. A hallmark of such autoimmune induction is the accompaniment of an immune shift, in which there is usually an initial skewing toward a Th2-like immune environment. Another heavy metal, lead (Pb), has also been found to induce a Th2 shift in mice. However, exposure of normal mouse strains to Pb does not appear to induce autoimmunity. In order to investigate whether mice genetically predisposed to murine systemic lupus erythematosus (SLE) are susceptible to a Pb-induced exacerbation of lupus, males and females of four New Zealand mixed (NZM) mouse strains, along with BALB/c and C57Bl/6 controls, were administered three 100-microliter intraperitoneal injections of either 1.31 mM lead or sodium acetate per week for 3 wk. The four NZM strains chosen, NZM391, NZM2328, NZM88, and NZM2758, have differential genetic penetrance for SLE with variances in certain manifestations of the disease, but all of these strains naturally develop glomerulonephritis and produce high titers of anti-nuclear autoantibodies. The mice were prebled for baseline values and were bled directly after the injection period (d 1) and monthly thereafter for 5 mo. Sera were assessed for anti-double-stranded DNA titers, urea nitrogen levels, and creatine kinase activity, as well as four total immunoglobulin (Ig) G2a and IgG1 levels. Mortality and morbidity of the mice were also recorded. All NZM strains showed an acute, non-gender-based, susceptibility to Pb at d 1, but the control strains were unaffected. Over time, it became apparent that the strains diverged: The NZM391 strain showed gender-independent susceptibility to Pb enhancement of lupus manifestations and mortality; the NZM2328 strain exhibited gender-independent Pb susceptibility to manifestations, although only females had increased mortality; the NZM2758 strain exhibited non-gender-based elevations in urea nitrogen and creatine kinase activity levels; and the NZM88 strain displayed male susceptibility to anti-DNA and life span. Surprisingly, Pb increased the longevity of NZM88 and NZM2758 females. These results indicate that Pb indeed can exacerbate SLE in lupus-prone mice; however, even among lupus-prone strains, genetic differences determine the degree of exacerbation. Using the known phenotype and genetic differences, one can identify and characterize possible traits and loci associated with Pb susceptibility.