The objective of this study was to characterize the clinical pharmacokinetic profile of lofexidine after oral delivery. A single dose, cross-over study and a multidose study using healthy volunteers were conducted for that purpose. In the single dose study the average time to maximum concentration was observed at approximately 3 h for the single doses tested (1.2 mg dose and 2.0 mg). Area under the curve from time zero to infinity (AUC 0Γ1 ) demonstrated a degree of dose proportionality with a 1.72-fold increase as the dose increased by a factor of 1.67. Elimination rates and terminal halflives were comparable between dose levels. The average elimination rates for the 1.2 mg and the 2.0 mg doses were 0.063 and 0.065 h Γ1 , respectively. In the multidose study, the average maximum concentration observed after the first dose of 0.4 mg was 433 ng/L and ranged from 338 to 586 ng/L. This was slightly lower in proportion to the maximum concentration observed in the single dose study where C max was 1755 ng/L at the 1.2 mg dose (normalized to 585 ng/L for 0.4 mg dose) and for the 2.0 mg dose (normalized to 559 ng/L for 0.4 mg dose). The average time to maximum concentration (T max ) was 3.33 h which is comparable to values observed in the single dose study. The pharmacokinetic data indicate that lofexidine has a consistent profile. Steady state seems to be reached after 2 days on lofexidine, which is consistent with the lofexidine elimination half-life of approximately 11 h. Evaluation of the T max , elimination rate, and terminal half-life are consistent across all dose levels studied, suggesting that changing the dose does not affect the absorption or elimination rates of lofexidine HCl. Thus, although preliminary due to the limited number of subjects, these findings are the first to document lofexidine clinical pharmacokinetic parameters in healthy volunteers using a highly sensitive liquid chromatography tandem mass spectrometric analysis.