The Sputnik V COVID-19 vaccine, have shown excellent safety and efficacy against COVID-19 in phase 3 of the clinical trial. We provided independent evidence on side effects and immunogenicity following the administration of the Sputnik V COVID-19 in Iran. In this observational study, the healthcare workers who vaccinated with the Sputnik V COVID-19 vaccine within February and April 2021 were evaluated. Among a total of 13435 vaccinated healthcare workers, we received 3236 self-declaration reports of Sputnik V associated adverse events with the mean age 39.32±10.19 years old which 38.8% were men and 61.2% were women. The most common side effect was a pain in the injection site (56.9%), fatigue (50.9%), body pain (43.9%), headache (35.7%), fever (32.9%), joint pain (30.3%), chilling (29.8%) and drowsiness (20.3%). Side effects of the vaccine were significantly more frequent in females and younger individuals. Among a total of 238 participants, more than 90% after the first and second dose of vaccine had a detectable level of SARS-CoV-2 RBD antibody and SARS-CoV-2 neutralizing antibody. Although the overall the rate of adverse effects was higher than the interim results from randomized controlled trials, our findings support the manufacturer’s reports about the high humoral immunogenicity of vaccine against COVID-19.