Axial and lateral pressure loss in a 5 × 5 rod–bundle with a split-type mixing vane spacer grid was experimentally measured using differential pressure transmitters at different sub-channel Reynolds numbers (Re) and orienting angles. The geometrical parameters of the 5 × 5–rod bundle are as follows: they have the same diameter (D = 9.5 mm) and pitch (p = 12.6 mm) as those of real fuel rods of a typical pressurized water reactor (PWR), with a sub-channel hydraulic diameter (Dh) of 11.78 mm. The characteristics and resistance models of pressure loss are discussed. The main axial pressure loss is caused by the spacer grid, and the spacer grid generates additional wall friction pressure loss downstream of the spacer grid. The lateral pressure loss shows strong correlations with orienting angles and distance from the spacer grid. The lateral pressure loss shows a sudden burst in the mixing vanes region and a slight augmentation at z = 3Dh. After 3Dh, the lateral pressure loss decays in an exponential way with distance from the spacer grid, and it becomes constant quickly at z = 20Dh.