The binding of theophylline to plasma proteins was studied in samples from healthy adults at different pH values and drug concentrations and in samples from patients with chronic obstructive pulmonary disease (COPD). Binding determinations were performed by ultrafiltration and drug concentrations were measured by high performance liquid chromatography. Total plasma levels of theophylline did not influence the degree of the binding. The percentage of bound theophylline was positively correlated with pH both in vitro (r = 0.998, p less than 0.005) and in vivo (r = 0.579, p less than 0.005). Mean theophylline binding values in vivo (mean 56.3 +/- 12.5) and in vitro (mean 48.3 +/- 9.4) were significantly different. The increase in theophylline free levels detected in COPD patients was partially dependent on low pH values but the influence of other factors must also be considered. The therapeutic implications of altered theophylline binding are discussed.