The typical antipsychotics chlorpromazine (CPZ) and trifluoperazine (TFP) increase the mean molecular area (mma) of acidic, but not neutral, glycerophospholipids in monolayers at pH 7.36 measured by the Langmuir technique. The atypical antipsychotic olanzapine (OLP(1)) is structurally similar to TFP. We have therefore studied the effects of OLP on glycerophospholipid monolayers and in comparison with CPZ. Olanzapine (10 microM, in subphase, pH 7.36) influenced the isotherms (surface pressure versus mma) in monolayers of the neutral dipalmitoyl phosphatidylcholine (DPPC) and the acidic dipalmitoyl phosphatidylserine (DPPS) or 1-palmitoyl-2-oleoylphosphatidylserine (POPS) in the increasing order of mma: DPPS<DPPC<POPS at both lower and higher temperature. Thus, presence of an unsaturated acyl in PS increased the drug-induced effect on mma. The mma in the absence of drugs was lower at lower temperatures than at higher temperatures. OLP affected mma to a greater extent than CPZ, and caused the greatest interaction at surface pressure of 30 mN/m at higher temperatures. In contrast, CPZ gave the largest effect in the monolayers at surface pressure 30 mN/m at lower temperatures. CPZ did not alter the isotherms of DPPC, at lower or higher temperature, and only affected the packing of the DPPS and POPS monolayers. In contrast, OLP altered the isotherms of DPPC. It is suggested that the drugs affect the monolayer packing by intercalating between the glycerophospholipid molecules. Since CPZ has major side effects, while OLP has few, this may indicate that there is poor correlation between side effects and effects of the drugs on phospholipid monolayers.