Phenytoin is often used to prevent postcraniotomy seizures, but is not always effective. We investigate changes in plasma phenytoin level ([phenytoin]) following craniotomy. The [phenytoin] in 28 patients who were receiving phenytoin (oral/ intravenous) and undergoing a craniotomy were prospectively measured 24 h preoperatively, immediately pre- and postcraniotomy, 24 and 48 h postoperatively. Factors examined included patients' age, sex, pathology, preoperative [phenytoin], operative duration and blood loss. Fifteen patients had [phenytoin] concentrations outside the therapeutic range. Twenty-five patients experienced a decrease in [phenytoin] immediately postcraniotomy: pre-, post- and 24 h postcraniotomy mean [phenytoin] were 13.4, 10.0 and 12.9 mg/l, respectively. Preoperative [phenytoin], operative duration and blood loss had significant correlation with the decrease in [phenytoin] (p < 0.05). In conclusion, < 50% of the patients had therapeutic preoperative [phenytoin]. In most patients, [phenytoin] decreases by 26% after craniotomy and returns to preoperative level within 24 h. These may contribute to early postoperative seizure development.