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Objective To evaluate the effects of personalized exposure in vivo on level of physical activity and quality of life in patients with painful diabetic neuropathy. Design Randomized, single-case, ABC design. Subjects Twelve patients with painful diabetic neuropathy, age > 18 years, diabetes mellitus type II, Clinical Neurological Examination score > 5, Diabetic Neuropathy Symptom Score ≥ 1 and Douleur Neuropathique 4 Questions score ≥ 3. Methods The treatment consists of an Intensive screening, followed by an 8-week exposure in vivo intervention specifically adapted to the needs/risks of patients with painful diabetic neuropathy, and 6-months follow-up. Outcome measures included daily and non-daily measures of physical activity, quality of life, metabolic parameters, disability, depression, general and painful diabetic neuropathy-related anxiety, pain intensity and pain catastrophizing. Results Due to high drop-out rates (n = 6 during screening, n = 2 during treatment, n = 1 after treatment), only 3 participants completed the study. Slight, but non-significant, changes in physical activity and disability were observed. In quality of life, no changes were observed. Conclusion Analysis of the reasons for the high drop-out rate indicate that exposure in vivo may have added value in patients with painful diabetic neuropathy only for those patients: (i) whose daily life functioning is impaired mainly by the painful diabetic neuropathy; (ii) in whom painful diabetic neuropathy-related fears are exaggerated and irrational; (iii) in whom specific activities evoke the painful diabetic neuropathy-related fears; (iv) whose spouse and healthcare providers are involved in the treatment; and (v) who are willing to change their daily behaviour. Further research is needed into this subject. LAY ABSTRACT Painful diabetic neuropathy places a high burden on patients’ physical and emotional wellbeing. Patients with painful diabetic neuropathy may have several fears related to diabetes and pain (e.g. fear of pain, fear of falling), which can limit their physically activity in daily life. This study investigated the effects of a personalized rehabilitation treatment, exposure in vivo, which aimed to help people with painful diabetic neuropathy to overcome their fears, so that they could become more active in daily life and improve their quality of life. Slight improvements in physical activity and disability were seen. There were no changes in quality of life. The results of this study should be interpreted with caution, as there was a large number of drop-outs.