Adverse effects and venous blood ammonia concentrations were monitored over a period of 7 months in patients with epilepsy treated with valproate (VPA). During the 1st, 4th, 12th, 20th, and 28th weeks of therapy, blood samples for analysis of ammonia and anticonvulsants were taken immediately before the morning dose of VPA as well as 2 h after dosing. In all, 40 patients completed the follow-up; 16 of these (Group 1) received VPA alone, while the remaining 24 (Group 2) were treated simultaneously with VPA and other anticonvulsants (phenobarbital, phenytoin, and/or carbamazepine). In Group 1 patients, a slight though significant increase in ammonia concentrations was found during long-term VPA treatment; this trend was even more pronounced in Group 2 patients. The difference between postdose and predose ammonia levels in Group 2 patients was significant at each of the five follow-up examinations. In contrast, no such difference was demonstrated in patients of Group 1. VPA concentrations were found to be consistently higher in Group 2 patients than in Group 1. Twenty-three patients complained of various long-term adverse effects, while the other 17 remained symptom-free. The adverse effects reported included drowsiness, tremors, weight gain, hair loss, and gastrointestinal symptoms. Our data confirm the previously suggested hypothesis that changes in venous blood ammonia are particularly evident in patients taking VPA in combination with other antiepileptic drugs, such as phenobarbital and phenytoin.