Interdependencies between projects have come to play a more active role in the decision on IT/IS portfolios and their constituent projects. However, managing these interdependencies can be a complex task, especially when the number and degree of interdependencies among projects are high. In times of uncertainty, unexpected challenges can seriously disrupt projects and, consequently, their interdependencies. This may threaten the project portfolio from achieving its final goal. The study aims to investigate the difficulties associated with managing project interdependence along the development cycle of the project portfolio. The study was conducted using a qualitative approach and semi-structured interviews with managers from four leading organizations in Saudi Arabia. The findings reveal three main categories of factors that increased the difficulty of managing project interdependencies in large IT/IS project portfolios: insufficient understanding of human responsibilities in the whole portfolio, unpredictability of the environment, and technology barriers and constraints.