Medullary thyroid cancer (MTC) accounts for 4% of all thyroid cancers and originates from the parafollicular C-cells. Prostate-specific membrane antigen (PSMA) is known for its expression in the epithelium of prostate cancer and has been demonstrated to be useful both for therapeutic and diagnostic purposes as a so-called theranostic target. As PSMA is also expressed in the neovasculature of other solid tumor types, our aim was to assess PSMA expression and its prognostic role in MTC. Tissues from patients that underwent surgery for MTC between 1988 and 2014 in five tertiary referral centers in The Netherlands were included in a tissue microarray. Using immunohistochemistry, total numbers of PSMA and CD31-positive microvessels were evaluated. Results showed that 92% of MTC expressed PSMA in the neovasculature, whereas the tumor cells were consistently negative. The average number of PSMA-positive microvessels did not differ significantly between the primary tumor and initial lymph node metastases (P = .09), nor between initial and recurrent lymph node metastases (P = 1.00). The PSMA score was found to be correlated with progression-free survival and overall survival. In multivariate analysis, a higher number of PSMA-positive microvessels was associated with favorable prognosis (odds ratio 3.6; 95% confidence interval 1.0-12.8; P = .05). In conclusion, over 90% of MTC appears to express PSMA in the neovasculature. A higher number of PSMA-positive microvessels is prognostically favorable. Since it is highly expressed in MTC, PSMA is an interesting novel target for imaging and potentially also as a target for peptide radioligand therapy in MTC.