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Background: Due to their immunocompromised conditions, hemodialysis (HD) patients are at high risk of being infected with SARS-CoV-2 with poor clinical outcomes. We explored safety, efficacy and variability factors associated with vaccine immune response in these patients. Methods: From 18 January to 30 April 2021, 87 HD patients were enrolled in this study and subdivided in two sub-groups: SARS-CoV-2 positive prior to vaccination and naïve patients. The vaccination protocol included two intramuscular shots of the mRNA vaccine at a 28-day interval. The vaccine response was evaluated one month after the first and second shots by measuring anti-S antibody titers. Findings: 44% of the patients studied, were women; median age was 58 years. One month after the first shot, 64.3% of patients had anti-S antibody titers < 50 U/mL while 96.5% had anti-S antibody titers > 250 U/mL one month after the second shot. We show that the anti-SARS-CoV-2 spike mRNA vaccine elicits a great tolerability in HD patients. Importantlly, the vaccine response is characterized by a higher rate of seroconversion than conventional vaccination, as we have shown for the hepatitis B vaccine. We highlight two major factors of variability of the vaccine response. First, pre-exposure to SARS-CoV-2 boosts humoral response, as 95% of SARS-CoV-2 positive patients developed anti-S antibody titers > 250 U/L just after the first shot. Secondly, on the contrary fluid overload strikingly appears, limiting the vaccine response, as 84% of HD patients with fluid overload elicit lower anti-S antibody titers after the first shot. Interpretation: Our findings show that the immunogenic profile induced by mRNA vaccines in HD patients represents a promising a protective strategy that is associated with greater tolerability. Fluid overload may be considered as a novel factor that hinders the immune response in HD patients and further studies will be needed to investigate this working hypothesis.