We aimed to describe the burden represented by potentially inappropriate medications (PIMs) in chronic polypharmacy in France. We conducted a nationwide cross-sectional study using data from the French National Insurance databases. The study period was from 1 January 2016 to 31 December 2016. Chronic drug use was defined as uninterrupted daily use lasting ≥6 months. Chronic polypharmacy was defined as the chronic use of ≥5 medications, and chronic hyperpolypharmacy as the chronic use of ≥10 medications. For individuals aged ≥65 (older adults), PIMs were defined according to the Beers and Laroche lists, and for individuals aged 45–64 years (middle-aged) PIMs were defined according to the PROMPT (Prescribing Optimally in Middle-aged People’s Treatments) list. Among individuals with chronic polypharmacy, 4009 (46.2%) middle-aged and 18,036 (64.8%) older adults had at least one chronic PIM. Among individuals with chronic hyperpolypharmacy, these figures were, respectively, 570 (75.0%) and 2544 (88.7%). The most frequent chronic PIM were proton pump inhibitors (43.4% of older adults with chronic polypharmacy), short-acting benzodiazepines (older adults: 13.7%; middle-aged: 16.1%), hypnotics (6.1%; 7.4%), and long-acting sulfonylureas (3.9%; 12.3%). The burden of chronic PIM appeared to be very high in our study, concerning almost half of middle-aged adults and two-thirds of older adults with chronic polypharmacy. Deprescribing interventions in polypharmacy should primarily target proton pump inhibitors and hypnotics.