A new radioimmunoassay (RIA) procedure for the quantitation of chlorpheniramine in plasma is described. The assay allows the determination of chlorpheniramine levels up to 96 h after oral administration of a single 4-mg tablet to healthy volunteers. This procedure was sensitive to a 156-pg/mL plasma concentration when a 100-microL plasma sample was used. The mean coefficient of variation over the linear range of the assay from 0.156 to 20 ng/mL was 3.79%. The specificity of the assay was investigated, and the antisera showed 7% cross-reactivity with the N,N-didemethyl analogue and 17% cross-reactivity with the N-demethyl analogue. This high degree of specificity was also evident from the findings that the plasma concentrations determined by this newly described RIA procedure in samples of two healthy male volunteers who were administered 4 mg of chlorpheniramine maleate orally gave a strong correlation (r2 = 0.88) with values obtained by an HPLC-UV procedure. The antiserum cross-reacted 100% with brompheniramine and, thus, can be used for its analysis in plasma. The described RIA procedure is precise, simple, and capable of handling a large number of plasma samples with a minimal turnaround time.