AbstractHigh rates of lung failure have been reported in haematological patients after SARS‐CoV2 infection. An early administration of monoclonal antibodies or anti‐virals may improve the prognosis. Oral anti‐virals may have a wider use independently of the genetic variations of the virus. Prospective data on anti‐virals in haematological malignancies (HMs) are still lacking. Outpatients diagnosed with HM and early COVID‐19 infection were prospectively treated with the oral anti‐virals nirmatrelvir/ritonavir and molnupiravir. Incidence of lung failure, deaths and adverse events was analysed. Long‐term outcome at third month was evaluated. Eighty‐two outpatients were evaluable for the study objectives. All patients had been treated for their HM within 12 months. COVID‐19‐related lung failure was 23.1%. Active HM (aOR = 4.42; p = 0.038) and prolonged viral shedding (aOR = 1.04; p = 0.022) resulted independent predictors of severe infection. The vaccination with three to four doses (aOR = 0.02; p = 0.001) and with two doses (aOR = 0.06; p = 0.006) resulted protective. COVID‐19‐related deaths at 28 days were 6.1%. All‐cause mortality at 90‐day follow‐up was 13.4% (n. 11) and included opportunistic infections and cardiovascular events. In conclusion, this approach reduced the incidence of lung failure and specific mortality compared to previous cohorts, but patients remain at high risk of further complications.