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Valproic acid (VPA) is an effective antiepileptic drug and mood stabilizer. A key characteristic of VPA is its high and saturable protein binding at higher concentrations. Although the unbound concentration of VPA is responsible for its pharmacological activity, total drug concentrations are monitored in routine clinical practice. Therapeutic drug monitoring (TDM) of unbound VPA is recommended for specific clinical situations. The goal of this study was to evaluate TDM requests for unbound VPA in clinical practice.All TDM requests at our laboratory for unbound VPA in 2014 and 2015 were evaluated retrospectively. In patients with potentially toxic unbound VPA concentrations (ie, >12 mg/L), we evaluated whether toxicity was noted and whether the dose adjustment advice was followed. Total and unbound VPA concentrations were measured by means of a validated immunoassay.A total of 273 unbound VPA serum concentrations in 132 different patients were analyzed. The main reasons for unbound VPA TDM were decreased renal function (34%) and a low serum albumin (27%). The median (range) unbound VPA concentration was 9.8 (2.5–47.6) mg/L. In 49 patients (37%), the initial unbound VPA concentration was above the threshold of 12 mg/L, potentially resulting in toxicity. Only 6 of these 49 patients had elevated total VPA concentrations. Clinical toxicity was noted in 38 of the 49 patients (77.6%) with elevated unbound VPA concentrations. Toxicities included drowsiness (n = 26), decreased consciousness (n = 4), rigidity (n = 2), and confusion (n = 2). In 36 of the 38 patients with elevated unbound VPA concentrations and clinical toxicity, a dose reduction was applied. In 27 of 36 patients who had their dose reduced, dose reduction was associated with improvement or resolution of VPA toxicity.TDM of unbound VPA is an important tool to manage VPA therapy in selected, vulnerable patients.