In this retrospective, propensity-score-matched case–control study, we have demonstrated for the first time that early therapy with mAbs or antivirals against acute SARS-CoV-2 infection is able to reduce the risk of occurrence of long COVID syndrome. Long COVID represents a broad and very heterogeneous clinical entity, with pathophysiological mechanisms which have not been fully elucidated and, consequently, have a lack of established therapies or prophylaxis [12,13,14,15,16]. In this large Italian cohort of COVID-19 patients, we reported an occurrence of long COVID in approximately 28% of cases, almost confirming most epidemiological available data [12,13,14,15,16]. Moreover, subjects affected by long COVID in our study population experienced a wide spectrum of symptoms, mainly dyspnea, fatigue and neuropsychiatric concerns that negatively affected quality of life, as previously described [12,13,14,15,16]. Taken together, our results contribute to further highlighting the importance of a follow-up for those subjects who experienced SARS-CoV-2 infection, with the aim to better identify patients at risk. In this context, we have noticed that age and female gender were independently associated with long COVID occurrence, confirming what has been already observed [16,17]. Of interest, we also reported that patients who developed long COVID more commonly experienced a hospital admission during acute SARS-CoV-2 infection. In the literature, the relationship between the severity of COVID-19 and the incidence of long COVID is controversial: for example, some authors have documented that hospitalization for COVID-19 is not an independent risk factor for long COVID [18]. In our study population we reported that hospitalization was directly associated with a higher risk for long COVID occurrence at univariate logistic regression analysis, but not at multivariate model. Our explanation to that observation is based on a clinical issue: it is well established that patients affected by multiple comorbidities are at high risk for COVID-19 progression and, consequently, for hospitalization [19]. Assuming a biological plausibility, it is possible to speculate that there was a co-linearity between both variables—hospitalization and comorbidities—as suggested by the multivariate model in which patients with at least three comorbidities have a 3threefold higher risk of long COVID occurrence. Therefore, when stratifying risk for post-COVID sequelae, patients’ comorbidities and clinical complexities, rather than hospitalization, should be considered. On the other hand, increasing evidence suggest that the relationship between COVID-19 and comorbidities is bidirectional since SARS-CoV-2 infection can indeed exacerbate already-known chronic disease, or trigger new-onset illness [20,21,22,23,24,25,26,27]. This close relationship may be mostly attributed to a pathophysiological common soil between COVID-19 and comorbidities, characterized by endothelial damage, and increased inflammatory and thromboembolic burden [28,29]. Currently, given the lack of data about a treatment for clinically overt long COVID, a prophylactic strategy that prevents both the progression of COVID-19 and the occurrence of comorbidities’ complication, could be crucial. In this context, in our study population subjects with vaccination against SARS-CoV-2 had a reduced risk of long COVID, supporting the hypothesis that preventing disease progression could be important in preventing also long-term sequelae, as previously described [30]. Despite data confirming effectiveness of vaccination, we have demonstrated for the first time that mAbs and antivirals significantly reduced the risk of long COVID by 56%, with an excellent safety profile. Moreover, after elimination of potential bias and confounding factors in the propensity-score-matched case–control analysis, we observed a lower occurrence of long COVID in the treated group in comparison with the untreated control group (11% vs. 34%; p = 0.001). Taken together, these results are of significant clinical relevance because they could provide physicians with an additional treatment option for long COVID, based on the early administration of mAbs or antivirals, with the aim of reducing the risk of both disease progression and long-term sequelae.