Immunotherapy with convalescent plasma (CP) has been used in the past in several different infectious diseases and proposed as a potential therapeutic option in patients with COVID-19. However, a clear benefit was never demonstrated and randomized clinical trials (RCTs) conducted in different populations of COVID-19 patients showed contrasting results. In general, current evidences suggest that CP in patients with moderate to severe COVID-19 does not reduce the progression to severe respiratory failure or death within 30 days. However, currently published RCTs have several limitations. The administration of plasma with low titer of neutralizing antibodies (NAbs), the use of suboptimal surrogate serological tests to determine NAbs titer, the delayed administration of CP from the onset of COVID-19 symptoms and the lack of information about antibody titer of recipients before CP infusion, are all limiting factors that may have affected the study results. Thus, a potential benefit of early (within the first 72 h from onset of symptoms), high titer CP in patients with mild COVID-19 (pO2/FiO2>300) cannot be definitively excluded. However, immunotherapy with monoclonal antibodies developed from CP demonstrated efficacy in reducing progression to severe COVID-19 and hospitalization and are today recommended in the early phase of COVID-19.