Previous reports from this laboratory have shown that penicillamine effectively reduces serum digoxin levels and is a clinically useful drug in correcting digoxin intoxication. To elucidate further the antidigitalis effects of penicillamine a prospective study was undertaken in 10 children aged 4--14 years with congestive heart failure. Plasma and intracellular erythrocyte concentrations of sodium, potassium, calcium as well as Na+/K+ and Na+/Ca++ ratios were measured before digitalization, 6 days after full digitalization while the patients were on maintenance doses of digoxin (0.02 mg/Kg/day, po, maximum 0.25 mg/day) and 6 hours after 1 Gm of oral penicillamine. After digitalization RBC Na+, Ca++, Na+/K+, and Na+/Ca++ increased, whereas RBC K+ levels decreased significantly. Administration of penicillamline not only reduced serum digoxin levels, but it also caused significant alterations in RBC electrolyte concentrations, toward pre-digoxin values. All values were significantly changed after penicillamine. Plasma and RBC magnesium levels were not altered significantly, neither after digitalization nor after penicillamine. It is concluded that in addition to RBC Na+ and K+ levels, intra-erythrocyte levels of calcium are sensitive indicators of digoxin effect; and that penicillamine reverses digoxin-induced RBC electrolyte alterations towards pre-digitalization values.