Two-phase flows are encountered in a wide range of technological and natural situations. In the last decade, advances in the available computing power have enabled to solve the underlying equations with computational fluid dynamics (CFD) using multi-phase models for the interaction between the different phases. In this study, a volume of fluid (VOF) solver in OpenFOAM is used to investigate the pressure profile in a co-current upward pipe flow of air and water. It is hypothesized that pressure drop events are caused by local buildup of the slower liquid, whereas conservation of volume flow rate forces the dense liquid to accelerate. The calculated pressure gradients are larger than the corresponding experimental data. It is shown that this mismatch might be caused by the evaluation of the momentum balance based on mixture properties; the mixture density increases the effective liquid obstruction and the corresponding pressure drop. Finally, the effect of these pressure fluctuations on the pipe’s vibration is studied using a one-dimensional independent rings structural model.