Aims of the study This study reports on the ethnobotanical and phytomedical knowledge in one of the oldest European Parks, the Abruzzo, Lazio and Molise National Park (Central Italy). We selected this area because we judged the long history of nature preservation as an added value potentially encouraging the survival of uses possibly lost elsewhere. Methodology In all, we interviewed 60 key informants (30 men and 30 women) selected among those who, for their current or past occupation or specific interests, were most likely to report accurately on traditional use of plants. The average age of informants was 65 years (range 27–102 years). Results The ethnobotanical inventory we obtained included 145 taxa from 57 families, corresponding to 435 use-reports: 257 referred to medical applications, 112 to food, 29 to craft plants for domestic uses, 25 to veterinary applications, 6 to harvesting for trade and another 6 to animal food. The most common therapeutic uses in the folk tradition are those that are more easily prepared and/or administered such as external applications of fresh or dried plants, and decoctions. Of 90 species used for medical applications, key informants reported on 181 different uses, 136 of which known to have actual pharmacological properties. Of the uses recorded, 76 (42%) concern external applications, especially to treat wounds. Medical applications accounted for most current uses. Only 24% of the uses we recorded still occur in people's everyday life. Species no longer used include dye plants ( Fraxinus ornus, Rubia tinctorum, Scabiosa purpurea, Rhus coriaria and Isatis tinctoria) and plants once employed during pregnancy, for parturition, nursing, abortion ( Asplenium trichomanes, Ecballium elaterium, Juniperus sabina and Taxus baccata) or old magical practices ( Rosa canina). Conclusions Our study remarked the relationship existing between the high plant diversity recorded in this biodiversity hotspot of central Apennines and the rich ethnobotanical knowledge. The presence of some very experienced young informants was related to the opportunities offered by living in a major protected area. However, to counter the disappearance of local ethnobotanical culture it would be important to incorporate its preservation among nature reserve activities.