Inclusion clusters with a size of several tens of micrometers were found to be inclined to early crack initiation, resulting in an abnormally reduced fatigue life. Fatigue tests were conducted to elucidate crack initiation behaviors of inclusion clusters in nickel-based powder metallurgy (P/M) FGH96 superalloy. The inclusion clusters with varying sizes and shapes located at grain boundaries are composed of Al2O3, MgO and ZrO2 particles. The inclusion cluster with large size within 25-35 μm, small average particle distance within 0-4 μm and large orientation relative to loading direction within 35-66° will be more likely to cause crack initiation. In particular, the inclusion clusters with large size and high aggregation degree experience extruding during processing and subsequent heat-treatments due to the difference in thermal expansion coefficient with the matrix behave multiple cracking before fatigue loading, thereby facilitating crack initiation in the surrounding matrix grains. Moreover, as the main cracking part of inclusion clusters, the Al2O3 particles exhibit self-cracking and interface debonding, owing to higher hardness and poorer deformation coordination degree with matrix compared to other component inclusion particles.