(1) Background: The pandemic wave produced by SARS-CoV-2 Omicron was characterized by milder clinical forms and high contagiousness. The vaccination rate against COVID-19 in Romania was approximately 42%. (2) Objectives: Comparison of the clinical severity in vaccinated patients compared to unvaccinated ones. (3) Methods: A retrospective cohort study was conducted on a group of 699 adult patients confirmed with COVID-19 who presented in the "Sf. Cuvioasa Parascheva" Infectious Diseases Clinical Hospital of Galati, Romania, between 1 January 2022 and 30 June 2022. The study compared the need for hospitalization, reinfections, demographic and comorbidity data, clinical and paraclinical parameters from the initial evaluation, and the ratio of unfavorable developments on subgroups chosen according to the vaccination status. (4) Results and Conclusions: Our study reveals that unvaccinated patients required hospitalization in 54.68% of cases, while fully vaccinated patients had a hospitalization rate of 40.72%, which was significantly lower than that of the unvaccinated group (p = 0.01); patients who received a booster dose had a hospitalization rate of 27.84% (p < 0.01, significantly lower than unvaccinated individuals; p = 0.01, significantly lower than fully vaccinated individuals); and among the four patients who received four doses, none required hospitalization. From the analysis of the two subgroups of hospitalized patients, we observed a significantly higher prevalence of radiological lesions, such as pulmonary opacities in the group of unvaccinated patients and a higher average duration of hospitalization, and serum values of D-dimers and blood-sugar at admission were significantly higher in unvaccinated patients. The higher presence of these parameters, which are indicators of severe progression in clinical studies, in the group of unvaccinated patients suggests the need to include them in the initial evaluation of the unvaccinated patients with COVID-19.The cumulative share of deaths and transfers in the ICU was higher in the group of unvaccinated patients, but the difference between the groups had no statistical significance. This study draws attention to the possibility of severe clinical forms among both vaccinated and unvaccinated populations, especially in the elderly and in patients with multiple comorbidities.