This study purposes to determine the prevalence of potential and clinical relevant Drug-Drug-Interactions (pDDIs) in institutionalized older adults and to identify the pertinent factors associated. We conduct an observational, multicenter and cross-sectional study during the last quarter of 2010. We selected a sample of 275 subjects (aged ≥ 65 years) from 10 nursing homes of Murcia (Spain) by a two-stage complex sampling. pDDIs were identified using the College of Pharmacists Database. We only considered pDDIs of clinical relevance, and thereafter the relevant factors were identified through uni-level and multi-level regression analyses. A total of 210 pDDIs were identified, 120 of which were considered clinically relevant (57.1%), affecting a total of 70 elderly (25.8%). Eight pharmacological groups made up 70.2% of the clinically relevant pDDIs. More clinically relevant DDIs were found in people suffering several pathologies (OR = 2.3; 95%CI = 1.4-4.5), and also in people who take ten or more drugs daily (OR = 9.6; 95%CI = 4.8-19.1), and people who take anti-inflammatory drugs (OR = 3.9; 95%CI = 1.4-10.4). This study reveals that clinically relevant pDDIs are very common in institutionalized elderly people, and that caregivers should aim at improving their practice in order to reduce the prevalence of this phenomenon.