In this article we analyze the reasons for catalytic promiscuity of a type VIII esterase with β-lactamase fold and the ability to cleave β-lactams. We compared the structure of this enzyme to those of an esterase of the same type without any lactamase ability, an esterase with moderate lactamase ability, and a class C β-lactamase with similar fold. Our results show that for these enzymes, the difference in the substrate specificity is sterically driven.