Background: Rituximab, a monoclonal antibody targeting CD20, has revolutionized the management of B-cell lymphoproliferative disorders and some immune conditions, significantly improving disease control and patient survival. Beyond its indisputable therapeutic benefits, rituximab can cause serious pulmonary adverse events, particularly interstitial lung disease (R-ILD). Diagnosing R-ILD is challenging due to nonspecific clinical and imagistic features, and its true incidence is possibly underestimated. Methods: We conducted a systematic review to synthesize current evidence on R-ILD, focusing on its incidence, diagnostic approaches, management strategies and clinical outcomes. A comprehensive search of PubMed/MEDLINE was performed using the term “rituximab induced interstitial lung disease” through August 2025. Relevant abstracts were screened, and full-text articles meeting the inclusion criteria were analyzed. Results: A total of 40 studies were retained after the search and screening, including case reports, case series and cohort studies of R-ILD. This condition was identified in both malignant and autoimmune disorders receiving rituximab, more frequently for combination regimens. Radiological manifestations were heterogeneous, and ground-glass opacities were the dominant pattern. Most R-ILD cases were reversible, but progression to chronic interstitial disease and fatal outcomes are possible. Cohort studies demonstrated variability in incidence, reported instances of successful rituximab reintroduction and suggested a protective effect of prophylactic trimethoprim-sulfamethoxazole against opportunistic pneumonitis. Conclusions: Although rare, R-ILD is a clinically significant complication of rituximab therapy. Early recognition and multidisciplinary management are essential, as most patients respond to corticosteroids, while severe cases may progress to respiratory failure or fatal outcomes.
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