In normal subjects, receiving multiple dosing regimens with Slophyllin and Phyllocontin in does calculated to give either 4 mg/kg or 6mg/kg theophylline free acid twice daily, serum theophylline concentrations were frequently less than 8 mg/l. Accumulation of the serum theophylline trough concentration occurred during the first 3 days of multiple dosing, and was followed by subsequent stabilization or even decline in serum theophylline trough concentrations. Side effects were noted with both Slophyllin and Phyllocontin, but only on the higher dosage regimens; they occurred within 24--48 hr of starting the drug, and tended to diminish if dosing was continued. The accumulation effect of serum theophylline concentrations may explain the timing of adverse effects, and should be avoided by starting methylxanthine therapy at a low dose. This may be increased after a few days. Further dosage adjustment may be necessary in some patients and should be facilitated by measurement of serum theophylline trough concentrations.