Importance Keratocystic odontogenic tumors of the jaw (KCOTs) affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog (HH) signaling pathway. Observations We examined the effect of vismodegib (an oral HH-pathway inhibitor) on KCOT size in BCNS patients enrolled in a clinical trial testing vismodegib for BCC prevention (NCT00957229), using pre and post-treatment MRIs. Four men and 2 women had pretreatment KCOTs, mean longest diameter 2.0cm (range: 0.7–3.3cm), occurring primarily in the mandible. Subjects were treated with vismodegib (150mg/day) for a mean 18 months (SD: 4.8, range: 11–24). Four subjects experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all subjects by 1.0cm (95% CI: 0.03, 1.94, p= 0.02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development. Conclusions and relevance Vismodegib shrinks some KCOTs in BCNS patients and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.