In this paper, we give an instability criterion for the Prandtl equations in three space variables, which shows that the monotonicity condition of tangential velocity fields is not sufficient for the well-posedness of the three dimensional Prandtl equations, in contrast to the classical well-posedness theory of the Prandtl equations in two space variables under the Oleinik monotonicity assumption of the tangential velocity. Both of linear stability and nonlinear stability are considered. This criterion shows that the monotonic shear flow is linear stable for the three dimensional Prandtl equations if and only if the tangential velocity field direction is invariant with respect to the normal variable, and this result is an exact complement to our recent work cite{LWY} on the well-posedness theory for the three dimensional Prandtl equations with special structure.