The Fueter mapping theorem gives a constructive way to extend holomorphic functions of one complex variable to monogenic functions, i.e., null solutions of the generalized Cauchy-Riemann operator in R 4 , denoted by D. This theorem is divided in two steps. In the first step a holomorphic function is extended to a slice hyperholomorphic function. The Cauchy formula for these type of functions is the starting point of the S-functional calculus. In the second step a monogenic function is obtained by applying the Laplace operator in four real variables, namely ∆, to a slice hyperholomorphic function. The polyanalytic functional calculus, that we study in this paper, is based on the factorization of ∆ = DD. Instead of applying directly the Laplace operator to a slice hyperholomorphic function we apply first the operator D and we get a polyanalytic function of order 2, i..e, a function that belongs to the kernel of D 2 . We can represent this type of functions in an integral form and then we can define the polyanalytic functional calculus on S-spectrum. The main goal of this paper is to show the principal properties of this functional calculus. In particular, we study a resolvent equation suitable for proving a product rule and generate the Riesz projectors.