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Background Nowadays polytherapy is widely used in older patients affected by comorbidity but it implies changing kinetics and dynamics which can increase the probability of negative drug interactions resulting in therapeutic failure and/or adverse drug reactions. Purpose The aim of this study was to retrospectively assess the prescriptions of discharged patients to assess potential drug interactions in terms of frequency and characteristics. Materials and methods The retrospective study was carried out considering the data within the period from 1 January to 31 March 2011. The study examined prescriptions with at least two drugs for patients older than 65 who were discharged from the General Medicine Unit of Azienda Ospedaliero Universitaria S. Maria della Misericordia in Udine. Drug interactions were identified and assessed using the Micromedex DrugReax System. Results The data involved 181 patients (44% male and 56% female): 12% in the range between 65 and 70 years, 79% in the range between 71 and 90 years and 9% of patients older than 90 years. Most patients had between 5 and 10 drugs (69%). The rest of them: 16% of patients had fewer than five drugs, 14% between 11 and 15 drugs and 1% more than 15 drugs. The authors analysed 1348 prescriptions. The therapeutic classes most frequently prescribed were: antithrombotic agent (161 prescriptions, 11.9%), diuretics (129 prescriptions, 9.6%), drugs for acid-related disorders and drugs for the heart (121 prescriptions, 9%). Furosemide (8.0%), pantoprazole (7.0%), acetylsalicylic acid and ramipril (5.3%) were the most frequently prescribed drugs. According to the Micromedex DrugReax database, only the treatments of 34 patients (19%) did not show potential drug interactions. The database responses pointed out 633 potential drug interactions, 47% of total prescriptions: 2% of minor, 78% of moderate and 20% of major severity. This meant that major-severity drug reactions were possible in 74 different prescriptions: ramipril-spironolactone (eight prescriptions) and simvastatin-warfarin (five prescriptions) being the most frequent. Conclusions The percentage of major-severity potential drug interactions was low. However, in order to improve the quality of healthcare, the key reading of the results was the opportunity to initiate a control procedure to prevent negative effects from the drug interaction. Clinical pharmacists should have a key role, using their expertise in a proactive exchange with the clinical prescriber when the treatment is decided. This might avoid potentially dangerous drug interactions that might lead to therapeutic failure and/or adverse drug reactions. Possible suggestions might include modification of time scheduling for drug administration. Finally clinical pharmacists should also educate patients to promote compliance with the drug administration regimen.