Anticholinergic burden (AB) is related to cognitive impairment (CI) and older complex chronic patients (OCCP) are more susceptible. Our objective was to evaluate the predictive value of ten anticholinergic scales to predict a potential CI due to anticholinergic pharmacotherapy in OCCP. An eight-month longitudinal multicentre study was carried out in a cohort of OCCP, in treatment with at least one anticholinergic drug and whose cognition status had been evaluated by Pfeiffer test twice for a period of 6–15 months. CI was considered when the Pfeiffer test increased 2 or more points. AB was detected using ten scales included on the Anticholinergic Burden Calculator. An ROC curve analysis was performed to assess the discriminative capacity of the scales to predict a potential CI and the cut-off point of AB that obtains better validity indicators. 415 patients were included (60.2% female, median age of 85 years (IQR = 11)). 190 patients (45.8%) manifested CI. Only the DBI (Drug Burden Index) showed statistically significant differences in the median AB between patients without CI and with CI (0.5 (1.00) vs. 0.67 (0.65), p = 0.006). At the ROC curve analysis, statistically significant values were obtained only with the DBI (AUC: 0.578 (0.523–0.633), p = 0.006). The cut-off point with the greatest validity selected for the DBI was an AB of 0.41 (moderate risk) (sensitivity = 81%, specificity = 36%, PPV = 51%). The DBI is the scale with the greatest discriminatory power to detect OCCP at risk of CI and the best cut-off point is a load value of 0.41.