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Purpose or Objective: the impact of COVID-19 has been overwhelming on cancer patients, who may be at higher risk of developing severe disease. Outstandingly, the aftermath on neoplastic patients is still largely unknown, remarkably regarding SARS-Cov-2 infection during radiotherapy. In this paper we report the experience of our Department, set in Lombardy, one of the regions most affected by the pandemic worldwide. Materials and Methods: data of cancer patients with ongoing on planned active treatment during the first and second “wave” of the pandemics were retrospectively analyzed. We compared a cohort of 402 cancer patients undergoing active treatment from February 24 to April 24, 2020 (when RT-PCR for SARS-Cov-2 on naso-pharyngeal swabs - NPS - were performed only in case of suggestive symptoms and/or contacts at risk) and a cohort represented by all the 636 patients with planned active treatment at Brescia University Radiation Oncology Department from October 31,2020 to February 06, 20121. In the latter group, all the subjects were screened for SARS-Cov-2 RNA with NPS before treatment start and every 10 days during treatment, as for institutional policy. Results: during the first “wave”, dedicated measures allowed an overall limited infection rate of 3.23% (13/402) and mortality of 1.24% (5/402);remarkably, 92.3% of the cases were detected before March 24. Nevertheless, mortality among COVID-19 patients was high (38.5%) and all the patients were symptomatic, with 46.5% presenting with severe disease. Globally, only 2.5% of ongoing treatments were suspended due to suspect or confirmed COVID-19 and 46.2% of positive patients carried on radiotherapy without interruption. During the second “wave”, a universal screening was implemented for all the patients with planned active treatment. A total of 1243 NPS was performed on 636 patients. The infection rate was 2.52% and 81.3% of the patients with a positive NPS was asymptomatic, two had mild disease and one severe disease that lead to death. All the patients already on treatment with mild or asymptomatic COVID-19 carried on the therapy with no or minimal delay. Median delay for patients with infection detected before treatment start was 16.5 days. Conclusion: detected incidence of COVID-19 was lower during the second outbreak in our patients (2.52% vs 3.23%), despite the extensive testing schedule that also substantiates the high rate of asymptomatic infections and the low mortality among COVID-19 patients (6.3% vs 38.5% during the first outbreak). A universal SARS-Cov-2 screening for all the patients with planned treatment might allow an early identification of COVID-19 patients, resulting in a timely management that could improve clinical outcomes and prevent the spread of the infection.