Background: α2-Adrenergic receptor (α2AR) agonists have become important adjuncts as anesthetic agents. They act by binding to α2ARs on the surface of cell membranes and cause centrally mediated sedation and analgesia. α2ARs also contribute to other aspects of physiologic regulation. Three subtypes of α2ARs (α(2-C2), α(2-C4), and α(2-C10)) have been described using molecular and pharmacologic techniques. We recently demonstrated species heterogeneity in the distribution of α1-adrenergic receptor subtypes, therefore making it imperative to analyze the distribution of α2AR subtypes in human tissues. This information may have importance in the understanding of potential side effects of administration of α2AR subtype-selective agonists for anesthesia in humans. Methods: RNA extracted from human tissues was analyzed by using quantitative ribonuclease protection assays to determine α2AR subtype messenger RNA (mRNA) expression in cardiovascular, central nervous system, and peripheral tissues. Results: α2AR mRNA is present in greatest concentrations in human kidney, followed by aorta > spleen > heart = lung. α(2-C4) mRNA predominates in heart, lung, aorta, cerebral cortex, cerebellum, spleen, kidney, and adrenal gland; α(2- C2) mRNA in liver; and α(2-C10) mRNA in pancreas and small intestine. Hence α2AR subtype mRNA distribution is tissue-selective and differs from that reported for rat. Conclusions: (1) On comparison with previous research we find possible species heterogeneity in α2AR subtype mRNA distribution (rat vs. human) for all three α2AR subtypes. (2) We demonstrate the presence and subtype heterogeneity of α2AR subtype mRNA in both brain and peripheral tissues. (3) Significant concentrations of α2AR mRNA are present in adult human heart. These findings have important implications for our understanding of human adrenergic physiology, provide a possible explanation for the existence of pharmacologically similar yet distinct α2AR subtypes, and may be important for the rational development of α2AR subtype-selective anesthetics and other therapeutic agents for use in treating human diseases.