Clonidine is a preferential alpha-2 agonist drug that has been used for over 35 years to treat hypertension. Recently, it has also been used as a preoperative medication and as a sedative/anxiolytic drug. This randomized, double-blind, placebo-controlled crossover clinical trial characterized the effects of oral clonidine pretreatment on intravenous catheter placement in 13 patients. Parameters measured included the bispectral index (BIS), Observer's Assessment of Alertness/Sedation Scale (OAA/S), frontal temporal electromyogram (EMG), 30-Second Blink Count (Blink), Digit Symbol Substitution Test (DSST), State Anxiety Inventory (SAI), fingertip versus forearm skin temperatures, and multiple questionnaires. Oral clonidine significantly decreased SAI scores, OAA/S, EMG, and Blink, but did not cause statistically significant BIS or DSST reductions. Subjects preferred oral clonidine pretreatment prior to venipuncture compared to placebo. Questionnaires also indicated that clonidine provided minimal sedation, considerable anxiolysis, and some analgesia. Fingertip versus forearm skin temperature differentials were decreased. Reduced fingertip versus forearm temperature differentials suggest increased peripheral cutaneous blood flow prior to venous cannulation. Oral clonidine pretreatment not only helped control patient anxiety and pain but also provided cardiovascular stability.