Low levels of total magnesium in sickle cell erythrocytes have been linked to increased sickling due to cell dehydration. We tested the null hypothesis that adult sickle cell anemia (SCA) patients have the same serum level of ionized Mg (Mg(2+)) and Ca(2+)/Mg(2+) ratio as healthy African Americans (AA) and healthy Caucasians (CAUC). We measured serum Mg(2+) and ionized calcium (Ca(2+)) with ion-selective electrodes and calculated the serum Ca(2+)/Mg(2+) ratios in patients with SCA and control groups (AA and CAUC). Seventy-four SCA patients and 61 controls were compared. SCA patients had significantly (P < 0.001) lower levels of serum Mg(2+) (0.52 +/- 0.05) compared to healthy AA (0.57 +/- 0.04) and CAUC (0.62 +/- 0.03). Eighty-six percent of the adult SCA patients had serum Mg(2+) levels below the mean for the AA group, and 96% of SCA patients were above the AA group's mean serum Ca(2+)/Mg(2+). Of the SCA patients studied, 25.6% (95% CI, 16.2-37.2%) had serum Mg(2+) levels below the racially adjusted lower limit of normal and 50% (95% CI, 38.1-61.9%) were above the upper limit of serum Ca(2+)/Mg(2+) for AA controls. By measuring serum Mg(2+) and Ca(2+), we were able to define a subset of SCA patients with hypomagnesemia and elevated Ca(2+)/Mg(2+) ratios, who may benefit from magnesium supplementation.