To further investigate fluid-structure–interaction problems that occur in the nuclear field such as the behavior of pressurized water reactor fuel rods, steam generator tubes, and other heat exchanger tubes, the flow-induced vibrations of two flexible tubes in tandem, side-by-side, and in staggered arrangements are investigated. First, a three-dimensional numerical model for fluid-structure interaction of flexible tubes in cross flow is developed. It is a three-dimensional fully coupled approach with solving the fluid flow and the structure vibration simultaneously. Second, results are presented in the form of force coefficients, dynamic response, trajectories, and wake vortex pattern. The effects of pitch ratio, tube arrangement, and flow velocity on the vibration response and the flow field characteristic are investigated. Critical pitch and critical velocity are obtained successfully. The critical velocity depends heavily on pitch ratio. Under the same pitch ratio and velocity, the side-by-side tubes have the maximum value of fluid force and vibration amplitude, followed by the staggered tubes the and tandem tubes in sequence. The trajectory and wake vortex pattern are highly dependent on tube arrangement, pitch ratio, and flow velocity.