We discuss an inverse problem in the theory of (standard) orthogonal polynomials involving two orthogonal polynomial families (P n ) n and (Q n ) n whose derivatives of higher orders m and k (resp.) are connected by a linear algebraic structure relation such asfor all n = 0, 1, 2, . . . , where M and N are fixed nonnegative integer numbers, and r i,n and s i,n are given complex parameters satisfying some natural conditions. Let u and v be the moment regular functionals associated with (P n ) n and (Q n ) n (resp.). Assuming 0 m k, we prove the existence of four polynomials Φ M+m+i and Ψ N+k+i , of degrees M + m + i and N + k + i (resp.), such thatthe (k − m)th-derivative, as well as the left-product of a functional by a polynomial, being defined in the usual sense of the theory of distributions. If k = m, then u and v are connected by a rational modification. If k = m + 1, then both u and v are semiclassical linear functionals, which are also connected by a rational modification. When k > m, the Stieltjes transform associated with u satisfies a non-homogeneous linear ordinary differential equation of order k − m with polynomial coefficients.