Objective: To investigate the characteristics of comorbidities and polypharmacy in middle-aged and elderly patients and assess the potential risk of drug-drug interactions. Methods: Retrospective analysis was carried out among the outpatients aged ≥45 years in the Second Medical Center of the PLA General Hospital from January to December 2016. The patient's comorbidities and polypharmacy were collected from the electronic medical records and annual physical examination reports. The frequency and grade of drug-drug interactions (DDIs) were summarized and ranked by Lexicomp(®) Drug Interactions database. Results: A total of 1 340 patients were enrolled in the study, of which 930 patients (69.40%) used 5 or more drugs, and 660 patients (49.25%) used 10 or more drugs. Multivariate analysis showed that age and the number of comorbidities were independent factors of excessive polypharmacy. The total frequency of detecting clinically significant DDIs (C+D+X) was 857 cases, with 0.8 cases per person by Lexicomp(®) Drug Interactions database. Among them, medications for nervous system accounted for the highest proportion of X-level DDIs. Conclusions: The comorbidities and polypharmacy in middle-aged and elderly patients are very prominent. More attention should be paid to drug interactions, especially in patients with neurological medication.