question: OBJECTIVES: To compare the clinical and epidemiological aspects associated with different predominant lineages circulating in Marseille from March 2020 to January 2021. METHODS: In this single-center retrospective cohort study, characteristics of patients infected with four different SARS-CoV-2 variants were documented from medical files. The outcome was the occurrence of clinical failure, defined as hospitalization (for outpatients), transfer to the intensive-care unit (inpatients), and death (all). RESULTS: 254 patients were infected with clade 20A (20AS), 85 with Marseille-1 (M1V), 190 with Marseille-4 (M4V) and 211 with N501Y (N501YV) variants. 20AS presented a bell-shaped epidemiological curve and nearly disappeared around May 2020. M1V reached a very weak peak, then disappeared after a month-and-a-half. M4V appeared in July presented an atypical wave form during seven months. N501YV has only recently appeared. As compared to 20AS, patients infected with M1V were less likely to report dyspnoea (aOR=0.50, p=0.04), rhinitis (aOR=0.57, p=0.04) and to be hospitalised (aOR=0.22, p=0.002). Patients infected with M4V were more likely to report fever than those with 20AS and M1V (aOR=2.49, p<0.0001 and aOR=2.30, p=0.007, respectively) and to be hospitalised than those with M1V (aOR=4.81, p=0.003). Patients infected with N501YV reported lower rate of rhinitis (aOR=0.50, p=0.001) and anosmia (aOR=0.57, p=0.02), as compared to those infected with 20AS. A lower rate of hospitalisation associated with N501YV infection as compared to 20AS and M4V (aOR=0.33, p<0.0001 and aOR=0.27, p<0.0001, respectively). CONCLUSIONS: The four lineages have presentations which differ from one other, epidemiologically and clinically. This supports SARS-CoV-2 genomic surveillance through next-generation sequencing.