• Homologous recombination due to coinfection is a driving force of viral evolution. • A specimen suggestive of coinfection was analyzed with sequencing and plaque assay. • Sequencing on primary sample is consistent with double viral population. • Plaque assay showed a recombinant strain deriving from Delta and Omicron. • Monitoring co-infections, particularly in patients who are immunocompromised, is needed. Recombination related to coinfection is a huge driving force in determining the virus genetic variability, particularly in conditions of partial immune control, leading to prolonged infection. Here, we characterized a distinctive mutational pattern, highly suggestive of Delta-Omicron double infection, in a lymphoma patient. The specimen was characterized through a combined approach, analyzing the results of deep sequencing in primary sample, viral culture, and plaque assay. Bioinformatic analysis on the sequences deriving from the primary sample supports the hypothesis of a double viral population within the host. Plaque assay on viral culture led to the isolation of a recombinant strain deriving from Delta and Omicron lineages, named XS, which virtually replaced its parent lineages within a single viral propagation. It is impossible to establish whether the recombination event happened within the host or in vitro ; however, it is important to monitor co-infections, especially in the exceptional intrahost environment of patients who are immunocompromised, as strong driving forces of viral evolution. [ABSTRACT FROM AUTHOR]