Valproic acid is an anticonvulsant that is strongly bound to serum albumin. The nonsteroidal antiinflammatory drugs mefenamic acid and fenoprofen are also strongly bound to albumin. We observed significant displacement of valproic acid from protein binding by mefenamic acid and fenoprofen at both therapeutic and slightly above therapeutic concentrations. The concentration of free valproic acid was higher in the uremic serum, as expected, but we observed no further displacement of valproic acid in the presence of mefenamic acid and fenoprofen. Known uremic compounds, hippuric acid and indoxyl sulfate, did not inhibit the interactions between valproic acid and mefenamic acid or fenoprofen. Treatment of uremic serum with activated charcoal at pH 3.0 removes endogenous interfering factors and corrects the binding defect of uremic serum for valproic acid. We observed significant displacement of valproic acid from protein binding by both mefenamic acid and fenoprofen in uremic serum after charcoal treatment. We conclude that endogenous factors are present in uremic sera that block interaction of valproic acid with mefenamic acid and fenoprofen.