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Background Drug interactions increase the risk of treatment failure, intoxication, hospital admissions, consultations and mortality. Computer-assisted prescription systems can help to detect interactions. Objectives To describe the drug–drug interaction (DDI) and drug–disease interaction (DdI) prevalence identified by a computer-assisted prescription system in patients with multimorbidity and polypharmacy. Factors associated with clinically relevant interactions were analysed. Methods Observational, descriptive, cross-sectional study in primary health care centres was undertaken in Spain. The sample included 593 patients aged 65–74 years with multimorbidity and polypharmacy participating in the MULTIPAP Study, recruited from November 2016 to January 2017. Drug interactions were identified by a computer-assisted prescription system. Descriptive, bivariate, and multivariate analyses with logistic regression models and robust estimators were performed. Results Half (50.1% (95% CI 46.1–54.1)) of the patients had at least one relevant DDI and 23.9% (95% CI 18.9–25.6) presented with a DdI. Non-opioid–central nervous system depressant drug combinations and benzodiazepine–opioid drug combinations were the two most common clinically relevant interactions (10.8% and 5.9%, respectively). Factors associated with DDI were the use of more than 10 drugs (OR 11.86; 95% CI 6.92–20.33) and having anxiety/depressive disorder (OR 1.98; 95% CI 1.31–2.98). Protective factors against DDI were hypertension (OR 0.62; 95% CI 0.41–0.94), diabetes (OR 0.57; 95% CI 0.40–0.82), and ischaemic heart disease (OR 0.43; 95% CI 0.25–0.74). Conclusion Drug interactions are prevalent in patients aged 65–74 years with multimorbidity and polypharmacy. The clinically relevant DDI frequency is low. The number of prescriptions taken is the most relevant factor associated with presenting a clinically relevant DDI.