This paper presents an experimental study to evaluate the use of spatially arranged self-tapping screws (STS) as shear connections for cross-laminated timber panels. Specifically, simple butt joints combined with crossed STS with different inclinations were investigated under quasi-static monotonic and reversed-cyclic loadings. The influence of the number and angle of insertion of screws, screws characteristics, friction and loading on the joint performance was explored. The yield load, load-carrying capacity and related slips, elastic stiffness, and ductility were evaluated considering two groups of tests performed on a total of 63 specimens of different size. Performance of connections with respect to the energy dissipation and loss of strength under cyclic loads was also investigated. It was shown that the spatial insertion angle of screws plays a key role in the performance of joints, not only because it relates to the shank to grain angle, but also because it affects the amount of wood involved in the bearing mechanism. Design models of STS connections are presented and discussed, and the test results are compared against analytical predictions. While good agreement for load-carrying capacity was obtained, the existing stiffness model seems less adequate with a consistent overestimation.