Abstract Recently a new sustained-release formulation of valproic acid has been developed in Japan. The sustained-release mechanism of the new formulation was different from the conventional formulation. The aim of the present study was to compare the pharmacokinetic characteristics of valproic acid in two sustained-release formulations. Different sustained-release formulations of valproic acid (Depakene R and Selenica R) were administered in a randomized cross-over fashion in repeated doses in 24 psychiatric patients. After ≥4 weeks administration of valproic acid once daily, blood samples were taken just before (0 h) and 8, 12, 24 h after the morning dose. Blood sampling was performed in the same manner in the same patients 4 weeks after switching from one to the other formulation of valproic acid. Serum concentrations of valproic acid at 0 h (50.7 ± 19.4 vs 44.9 ± 21.8 μg/mL, P < 0.05) and 24 h (52.3 ± 19.54 vs 6.2 ± 22.2 μg/mL, P < 0.05) were significantly higher during Selenica R than during Depakene R treatment, whereas the serum concentration of valproic acid at 8 h (49.7 ± 19.2 vs 62.4 ± 25.6 μg/mL, P < 0.01) was significantly lower during Selenica R treatment than during Depakene R treatment. Serum concentrations of valproic acid at 12 h were not different. The present study demonstrated that steady-state serum concentrations were different because of the different dissolution profiles. When a prescription for valproic acid is switched from one drug to the other, prescribers should be aware that the therapeutic drug monitoring data are not consistent.