Increasing awareness of sustainable building materials has led to interest in enhancing the structural performance of engineered wood products. This paper reports mechanical properties of cross-laminated timber (CLT) panels constructed with layers angled in an alternative configuration on a modified industrial CLT production line. Timber lamellae were adhesively bonded together in a single-step press procedure to form CLT panels. Transverse layers were laid at an angle of 45°, instead of the conventional 90° angle with respect to the longitudinal layers’ 0° angle. Tests were carried out on 20 five-layered CLT panels divided into two matched groups with either a 45° or a 90° configuration; an in-plane uniaxial compressive loading was applied in the principal orientation of the panels. These tests showed that the 45°-configured panels had a 30% higher compression stiffness and a 15% higher compression strength than the 90° configuration. The results also revealed that the 45°-configured CLT can be industrially produced without using more material than is required for conventional CLT 90° panels. In addition, the design possibility that the 45°-configured CLT can carry a given load while using less material also suggests that it is possible to use CLT in a wider range of structural applications.