Exposure to feared objects or situations is the most common and effective treatment for specific phobia and anxiety disorders in general (Chambless & Ollendick, 2001). The proposed underlying mechanism of exposure therapy is extinction. During the extinction process new non-fear memory traces are generated to inhibit old fear memories (Milad & Quirk, 2002). Although extinction effectively reduces the fear response in short-term testing, extinction gains are often not permanent. Return of fear is correspondingly a common problem in treatment for anxiety disorders (Mystkowski et al. 2002, 2006; Craske & Mystkowski, 2006). And there is a need to develop new treatment approaches that focus on enhancing treatment stability. Accumulating evidence indicates that targeting reconsolidation processes after successful fear memory reactivation might be critical for stable fear reduction (e.g. reactivation/extinction protocol from Schiller et al., 2010). But, a recent animal study points to that this might only apply to recent and not remote memories (as phobia-related fear memories) (Gräff et al., 2014). Consistent with this evidence, a translational approach with patients with spider phobia found reactivation prior to exposure treatment not to be more effective than exposure treatment alone (Shiban, 2014). The aforementioned animal study from Gräff et al., 2014 further showed that by using inhibitors of histone deacetylases (HDACis) during reconsolidation the neuroplasticity of remote fear memories could be reinstated and even remote memories persistently attenuated by a reactivation/extinction protocol (Gräff et al., 2014). In the present study, we aim to translate the evidence from Gräff et al, 2014 into a clinical application. Consequently, the current study examines, if the combination of HDACis and reactivation with exposure treatment leads to reduced return of fear in patients with spider phobia. Patients with spider phobia receive in a randomized, double-blind design placebo or the HDACi valproic acid (500mg) in combination with reactivation of remote fear memory before a 30-minutes exposure treatment. For exposure treatment, we use a virtual reality (VR) environment, which allows exposure in a standardized manner. Strength of phobic fear is evaluated by means of behavioral (behavioral avoidance test, BAT), subjective (Questionnaires, visual analogue scales) and psychophysiological (skin conductance, ECG) measures before and 3 months after exposure therapy in VR. A positive influence of a one-time application of valproic acid in combination with reactivation of remote fear memory before exposure treatment on the stability of fear reduction would not only have potential for the treatment of specific phobias and other anxiety disorders, but also other disorders treated with exposure as for example addictive disorders.