It is often difficult to differentiate between an exacerbation of systemic lupus erythematosus (SLE) and intercurrent pre-eclampsia in a patient with SLE since the manifestations of both entities include proteinuria and hypertension. This study was undertaken to determine wether serum C3 and C4 values can help distinguish SLE activity from pre-eclampsia. In 21 nonpregnant women of child-bearing age, the mean C3 level was 124 +/- 5 mg/dl and the mean C4 was 31 +/- 1 mg/dl. In 24 normal women in the third trimester of pregnancy, the C3 and C4 levels were elevated (165 +/- 4 mg/dl, p less than 0.001 versus nonpregnant control women; 37 +/- 2 mg/dl, p less than 0.01 versus nonpregnant control women, respectively). In 17 women in the third trimester of pregnancy with documented pre-eclampsia, the mean C3 level was 162 +/- 4 mg/dl, no different from that in normal pregnant women (p less than 0.001 versus nonpregnant control women; p = NS versus normal pregnant women), and the mean C4 was 29 +/- 3 mg/dl, lower than that found in normal pregnant women (p less than 0.02 versus normal pregnant women). Antinuclear antibody was absent at titers of less than 1:20 in all of these pre-eclamptic patients. In contrast, pregnant women with SLE has significantly lower C3 (103 +/- 13 mg/dl) and C4 (15.3 +/- 3.6 mg/dl) values during the third trimester of pregnancy than either normal pregnant women (p less than 0.001 for C3 and C4) or women with pre-eclampsia (p less than 0.001 for C3 and p less than 0.004 for C4) during the third trimester of pregnancy. Of the eight women with SLE in whom serial complement values were determined, three had falling C3 or C4 levels, and in each, there was a flare of SLE activity either during or immediately after pregnancy. None of the five patients with a rising C3 concentration had a flare of disease activity; however, pre-eclampsia developed in one of these patients, characterized by hypertension and proteinuria. Thus, measurement of serum C3 and C4 can help differentiate between SLE activity and pre-eclampsia, since both C3 and C4 are significantly lower in women with SLE than women with pre-eclampsia, and serum C3 and C4 concentrations rise during uncomplicated or pre-eclamptic pregnancy in women with SLE.