Clostridioides difficile stands as the leading cause of hospital acquired enteric infection in developed countries. In Argentina, the epidemiology of Clostridioides difficile infection (CDI) is currently poorly characterized. Therefore, we conducted a retrospective case-control study evaluating the prevalence of CDI in 249 stool samples collected between 2019 and 2023 in the Northwest region of Buenos Aires. The presence of C. difficile was detected by combining three techniques (EIA, PCR and toxigenic culture) in a diagnostic algorithm. Clinical and demographic data from patients was also analyzed to identify CDI-associated risk factors. 1 in 5 patients presented C. difficile as the etiological agent of diarrhea and the 80% of CDI+ cases carried toxigenic strains, most of which had been acquired in the community. Age ≥69 years, previous use of antibiotics, previous hospitalization and previous episodes of CDI emerged as predisposing factors for CDI in our study cohort. Blood parameters such as an elevated number of leukocytes and platelets, a decreased basophil count, and an increased urea concentration were identified as indicators of CDI. We also carried out a systematic review and a meta-analysis where we contrasted our results with 39 studies selected from different countries around the world. At the global level, the meta-analysis highlighted advanced age, previous consumption of antibiotics and previous hospitalization as CDI risk factors and the leukocyte count as an indicator of CDI. These results emphasize the importance of epidemiological studies and reveal crucial information for healthcare decision-making regarding CDI.