The formation and application of aerobic granules for the treatment of real wastewaters still remains challenging. The high fraction of particulate organic matter (X_S) present in real wastewaters can affect the granulation process. The present study aims at understanding to what extent the presence of X_S affects the granule formation and the quality of the treated effluent. A second objective was to evaluate how the operating conditions of an aerobic granular sludge (AGS) reactor must be adapted to overcome the effects of the presence of X_S. Two reactors fed with synthetic wastewaters were operated in absence (R1) or presence (R2) of starch as proxy for X_S. Different operating conditions were evaluated. Our results indicated that the presence of X_S in the wastewater reduces the kinetic of granule formation. After 52 d of operation, the fraction of granules reached only 21% in R2, while in R1 this fraction was of 54%. The granules grown in presence of X_S had irregular and filamentous outgrowths in the surface, which affected the settleability of the biomass and therefore the quality of the effluent. An extension of the anaerobic phase in R2 led to the formation of more compact granules with a better settling ability. A high fraction of granules was obtained in both reactors after an increase of the selection pressure for fast-settling biomass, but the quality of the effluent remained low. Operating the reactors in a simultaneous fill-and-draw mode at a low selection pressure for fast-settling biomass showed to be beneficial for substrate removal efficiency and for suppressing filamentous overgrowth. Average removal efficiencies for total COD, soluble COD, ammonium, and phosphate were 87 ± 4%, 95 ± 1%, 92 ± 10%, and 87 ± 12% for R1, and 72 ± 12%, 86 ± 5%, 71 ± 12%, and 77 ± 11% for R2, respectively. Overall our study demonstrates that the operating conditions of AGS reactors must be adapted according to the wastewater composition. When treating effluents that contain X_S, the selection pressure should be significantly reduced.