Abstract: In the presented work, the pressure drop prediction models for the helical cruciform fuel assembly with single-phase and two-phase flow were established. The air-water experimental system was established, and the test section of 4×4 helical cruciform fuel was assembled. The wire-mesh sensor technology was introduced for the void fraction measurement of air-water two-phase flow, which was inserted into the 4×4 helical cruciform fuel assembly. The single-phase frictional factor and two-phase friction multiplier under various conditions were obtained, respectively. Besides, the application of the classical pressure drop prediction models to the helical cruciform fuel assembly was analyzed. According to the results, the single-phase frictional factor curve of the helical cruciform fuel assembly in the transitional region was relatively smooth, and the significant inflection points were not observed. Rehme’s correlation matched well with the experimental frictional factor of helical cruciform fuel assembly with the Reynolds number larger than 3.5×10³. Conboy’s model was not applicable for the helical cruciform fuel assembly of the presented work, which means the geometrical parameters play significant role to the pressure drop of helical cruciform fuel assembly. A new prediction model with a geometrical factor was proposed for the single-phase frictional factor of the helical cruciform fuel assembly, and the prediction error is less than 6.4%. The experimental data of two-phase flow were analyzed based on the separated flow model, which demonstrats the applicability to the typical rod bundle channel. The two-phase friction multiplier of the helical cruciform fuel assembly is significantly larger than that of the pipe and bare rod bundle, which is attributed to the interaction between the gas phase and liquid phase in the helical cruciform fuel assembly. It is observed that the two-phase friction multiplier is decreased by increasing mass flowrate. The new prediction model for the two-phase friction multiplier of the helical cruciform fuel assembly was developed on the basis of the Chisholm’s model, and a mass flowrate dependent function is fitted for the Chisholm C coefficient. The prediction error for the new model is less than 6.4%. In the presented work, the applicability and effectiveness of wire-mesh sensor technology in the void fraction measurement of complex rod bundle channel was confirmed. The mathematical prediction methods for the pressure drop in the helical cruciform fuel assembly under the single-phase flow and two-phase flow conditions were developed. The presented work provides the fundamental models for the thermal-hydraulic analysis of the helical cruciform fuel assembly.