Digoxin serum concentration vs. time data have been described in the literature by a linear two-compartment model. When calculating the steady-state volume of distribution for digoxin after oral dosing, a computer fitting program is often used because of the complex first-order absorption, two-compartment model employed. Since computer programs are not always available, we computed and compared the steady-state volume of distribution/bioavailability for digoxin using both a model-independent (area) and compartmental approach. Six healthy subjects participated in the study; each received digoxin 0.2 mg in capsule form daily for ten days. The mean steady-state volume of distribution/bioavailability calculated by noncompartmental analysis was 785 L and the mean for compartmental analysis was 784 L. The small difference between methods suggests that area analysis offers a simpler alternative to computerized compartmental fitting to determine this parameter for digoxin.