The infection with Clostridium difficile (CDI), which appeared at epidemic level, after acquiring the germ of some fluoroquinolone resistance genes, initially considered nosocomial infection and adverse effect post-antibiotic therapy, is affecting more and more people without risk factors and extending into the community. This paper proposes an analysis of the two main antibiotics used in therapy: metronidazole and vancomycin, the evidence of efficacy in the literature and the chemical stability of antibiotics in simulated gastrointestinal fluid. Based on UV-Vis absorption spectra, it can be considered that there are no major changes in the chemical structure of the investigated drugs in the presence of gastro-duodenal conditions. Clinical impact of comparative treatment with metronidazole and vancomycin has also been studied, in a group of 720 CDI patients hospitalized during the period 1.01.2017-31.12.2018 in the Clinical Hospital St. Parascheva of Infectious Diseases Galati. From this group, two subgroups were selected, one of 284 patients receiving oral vancomycin treatment and one group of 62 patients receiving oral metronidazole for an initial nonsevere episode of CDI. The number of days from the beginning of the treatment until the normalization of the stool, the length of hospitalization, the number of days of antibiotic treatment and the percentage of relapses were comparable in the two groups, the percentage of deaths in the first 30 days from the episode of CDI was higher in the vancomycin-treated group, probably due mainly to the severe comorbidities of these patients. The conclusion of the study is that the treatments with metronidazole and vancomycin, of the initial episode, nonsevere of CDI are comparable as a therapeutic response, provided that the patients treated with metronidazole do not associate hepatic, renal or neurological impairment due to the risk of adverse reactions.