Background and purpose: Drugs with anticholinergic properties might have a negative impact on cognition, but findings are still conflicting. The association was evaluated between anticholinergic drugs and cognitive performance in primary care patients with first cognitive complaints. Methods: From April 2013 to March 2014, 353 general practitioners administered the Mini-Mental State Examination (MMSE) to patients presenting with first cognitive complaints. Drug history was collected and the anticholinergic cognitive burden (ACB) was scored and categorized as ACB 0, ACB 1 and ACB 2+. A mixed effect linear regression model was used to assess the association between ACB and MMSE score. Results: Of 4249 subjects entering the study (mean age 77 +/- 8.2 years, 66.4% women and mean years of schooling 8.9 +/- 4.5), 25.8% received at least one drug with anticholinergic action. According to multivariate analysis, and after adjustment for several confounders, subjects with ACB 2+ had a statistically significant lower MMSE score compared with those with ACB 0 (beta -0.63; 95% confidence interval -1.19; -0.07). Subjects with ACB 1 had a non-statistically significant lower MMSE score than those with ACB 0 (beta -0.11; 95% confidence interval -0.37; 0.15). Conclusions: Anticholinergic medication might affect cognitive function in people with first cognitive complaints. Alternatives should be taken into account when possible, balancing the benefits and harms of these medications.