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The ionization and lipophilicity behavior of the antihistamine (H₁-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5−7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log P^Z = 1.5), whereas its H-bonding capacity is relatively large (Δlog P^Z ≥ 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from “second-generation” antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg^-1 …