Epidemiology of Clostridium difficile is characterized by worldwide increase of C. difficile infections (CDI) and the emergence of new epidemic outbreak strains with the capacity for global spreading. Long-term local surveillance at the University of Saarland Medical Center between 2000 and 2013 shows that the incidence rate of laboratory-confirmed CDI was influenced by local epidemiology as well as by testing strategies. Since 2008, molecular typing of C. difficile was regularly performed for symptomatic hospitalized patients by surface-layer protein A sequence typing (slpAST), which is an established highly standardized technique for genotyping of C. difficile. The results were assigned to known ribotypes for better comparison to international data. It could be demonstrated that distribution of genotypes was different between age groups. Older patients were predominantly infected with ribotype 001 and 027, whereas ribotype 027 was not detected in the pediatric population. Molecular typing of German isolates sent to the advisory laboratory between 2011 and 2013 revealed that ribotype 027 is present with high percentages in most German regions except for the very North. In conclusion, optimized testing of all hospitalized patients with diarrhea should be generally implemented to avoid under-diagnosis of C. difficile infection. Ribotype 027 is highly prevalent in Germany, but its infections are restricted to older patients, while absent in children. Molecular typing of suspected hospital outbreaks and of patients with severe or recurrent disease may help to better understand virulence and epidemic spreading of C. difficile.