This study aimed to examine the physical and mental Quality of Life (QoL) trajectories in prostate cancer (PCa) patients participating in the Pros-IT CNR study. QoL was assessed using the Physical (PCS) and Mental Component Score (MCS) of Short-Form Health Survey upon diagnosis and two years later. Growth mixture models were applied on 1158 patients and 3 trajectories over time were identified for MCS: 75% of patients had constantly high scores, 13% had permanently low scores and 12% starting with low scores had a recovery; the predictors that differentiated the trajectories were age, comorbidities, a family history of PCa, and the bowel, urinary and sexual functional scores at diagnosis. In the physical domain, 2 trajectories were defined: 85% of patients had constantly high scores, while 15% started with low scores and had a further slight decrease. Two years after diagnosis, the psychological and physical status was moderately compromised in more than 10% of PCa patients. For mental health, the trajectory analysis suggested that following the compromised patients at diagnosis until treatment could allow identification of those more vulnerable, for which a level 2 intervention with support from a non-oncology team supervised by a clinical psychologist could be of help.