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Arterial blood gas (ABG) sampling is a painful procedure with no perfect technique for quelling the discomfort. An ideal local anesthesia should be rapid, easy to learn, inexpensive, and noninvasive. This study was aimed to compare pain levels from ABG sampling performed with vapocoolant spray in comparison to placebo. We hypothesized that pretreatment with the vapocoolant would reduce the pain of arterial puncture by at least 1 point on a 10 point verbal numeric scale. We have evaluated the effectiveness of a vapocoolant spray in achieving satisfactory pain control in patients undergoing ABG sampling in this randomized placebo controlled trial. Eighty patients were randomized to 2 groups: group A, who received vapocoolant spray, and group B, who received water spray as placebo (Control group). Puncture and spray application pain was assessed with numerical rating scale (0, the absence of pain; 10, greatest imaginable pain) and number of attempts was recorded. The pain score during ABG sampling was not lower in group A compared with group B significantly (4.78±1.761 vs. 4.90±1.837; P: 0.945). This study showed that while the spray exerts more application pain, the number of attempts required for ABG sampling was not significantly lower in group A compared with group B (1.38±0.54 vs. 1.53±0.68; P= 0.372). Vapocoolant spray was not effective in ABG pain reduction, had milder application pain compared to placebo (P< 0.05), but did not reduce sampling attempts. At present, this spray cannot be recommended for arterial puncture anesthesia, and further study on different timing is necessary.