We have examined the influence of genetic and other factors on the serum concentration of the fourth component of complement (C4) in four patients with systemic lupus erythematosus (SLE) studied over 3 to 8 years. Complement allotyping was performed to determine the number of C4 null genes in each patient. Two patients with C4 null genes had relatively low serum C4 concentrations with normal serum anti-DNA binding and no evidence of active disease. By contrast two patients without null alleles appeared to be consuming C4 when the serum C4 concentrations were within the conventional reference range. We therefore propose the use of appropriate reference ranges adjusted for the number of null alleles. Such adjusted reference ranges may improve the utility of serum C4 concentration in monitoring disease activity.