In enzymology, a 4-hydroxymandelate synthase (EC 1.13.11.46) is an enzyme that catalyzes the chemical reaction

4-hydroxyphenylpyruvate + O₂ ${\displaystyle \rightleftharpoons }$ 4-hydroxymandelate + CO₂

Thus, the two substrates of this enzyme are 4-hydroxyphenylpyruvate and oxygen, whereas its two products are 4-hydroxymandelate and carbon dioxide.

This enzyme belongs to the family of oxidoreductases, specifically those acting on single donors with O₂ as oxidant and incorporation of two atoms of oxygen into the substrate (oxygenases). The oxygen incorporated need not be derived from O₂. The systematic name of this enzyme class is 4-hydroxyphenylpyruvate:oxygen oxidoreductase (decarboxylating). This enzyme is also called 4-hydroxyphenylpyruvate dioxygenase II.