BACKGROUND: With multimorbidity increasing among older people, polypharmacy and the use of potentially inappropriate medications (PIMs) are assuming a prominent role in the life of the geriatric population. OBJECTIVE: To investigate the association of polypharmacy and PIM use with a wide range of factors in older people with mild cognitive impairment (MCI) to mild dementia. METHODS: The study population comprised 160 outpatients with a Clinical Dementia Rating of 0.5-1 and a Mini-Mental State Examination score of 20-30. Patients were classified as receiving polypharmacy when they took ≥5 different medications at the same time. PIMs were identified using the STOPP-J criteria. Cognitive, neuropsychological, nutritional, and physical function tests were performed and body measurements taken. Quality of life (QOL) was assessed using both components of the EQ-5D scale, the index score and the visual analogue scale (QOL VAS). A comorbidity index was calculated for all participants. RESULTS: PIM use was significantly associated with lower scores on the verbal fluency (initial letters) test and QOL index. Participants receiving polypharmacy showed an increased likelihood of worse frailty status and lower QOL VAS score. The number of medications was significantly associated with a worse frailty status. CONCLUSION: In a geriatric population with MCI to mild dementia, PIM use was associated with lower verbal fluency (initial letters) score and lower QOL, while the presence of polypharmacy was correlated with a worse frailty status and lower QOL. The number of medicines, instead, was correlated with a worse frailty status only.