The relative bioavailability of a generic digoxin tablet formulation was investigated according to proposed FDA guidelines. After administration of digoxin in three different oral formulations on separate occasions to 12 subjects, multiple serum samples were obtained over the first 5hr and assayed for digoxin by radioimmunoassay. The average 0-5-hr area under the serum digoxin concentration-time curve (A UC) for the generic tablet was 99.6% of the combined mean of the average A UC values for the reference tablet and a solution. In addition, the average peak heights, peak times, and AUC values for the two tablet formulations were not significantly different. The currently proposed FDA method of data analysis utilizes a combination of the means of three experimental measurements and provides no measure of the variability of the relative bioavailability estimate. Three other methods of data analysis that do provide variance estimates were evaluated: (a) the FDA method on an individual subject basis followed by averaging, (b) a logarithmic transformation of the AUC values, and (c) comparison of the AUC values of the generic and reference tablets using a paired t-test. A consideration of the experimental design required by the FDA and the statistics involved indicated that the last method may be the most appropriate for examination of the bioavailability of digoxin tablets relative to a market standard. It is also suggested that the proposed regulations be amended to make the standard a solution rather than a specific manufacturer’s product.