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Rat primary hepatocytes were incubated with midazolam (which is metabolized mainly by CYP3A2) at 37, 32 or 28\u2009\u00b0C. The Michaelis\u2013Menten constant (<jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>) and maximum velocity (<jats:italic>V<\/jats:italic><jats:sub>max<\/jats:sub>) of midazolam were estimated using the Michaelis\u2013Menten equation. The<jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>of CYP3A2 midazolam remained unchanged, but the<jats:italic>V<\/jats:italic><jats:sub>max<\/jats:sub>decreased at 28\u2009\u00b0C. In rats, whose temperature was maintained at 37, 32 or 28\u2009\u00b0C by a heat lamp or ice pack, the plasma concentrations of midazolam were higher, whereas those in the brain and liver were unchanged at 28\u2009\u00b0C. The tissue\/plasma concentration ratios were, however, increased significantly. The unbound fraction of midazolam in serum at 28\u2009\u00b0C was half that at 37\u2009\u00b0C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding. 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