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The aim of this study is to observe the influence of Medication-Related Osteonecrosis of the Jaw (MRONJ) on the physical and mental conditions of cancer patients using a Quality of Life (QoL) questionnaire during regular dental practice measures. Twenty cancer patients (8 males and 12 females) with established MRONJ were enrolled in the “MoMax” (Oral Medicine and Maxillofacial) project of the Department of Oral Sciences and Maxillofacial Surgery at “Sapienza” University of Rome, and were included in the study. The 12-item Short Form Survey was used to evaluate the QoL. Statistical analysis revealed a significant difference for Mental Component Summary (MCS) scores based on age (<i>p</i> = 0.018). The regression analysis revealed that the Physical Component Summary (PCS) scores were negatively influenced by the anti-resorptive medication duration (<i>p</i> = 0.031 and β = −1.137). No significant differences were observed with the other variables considered. The QoL of cancer patients is generally deteriorated and MRONJ may cause a further negative impact. This study highlights the possible need to include psychosocial and physical evaluations in the management process of MRONJ in cancer patients.