Lung cancer is the leading cause of cancer deaths. Despite optimal diagnosis and early treatment, many patients die of recurrent disease. There are no sufficiently useful biomarkers to predict the risk of tumor recurrence. Here, we show that expression of histone macroH2A1.1 and macroH2A2 predicts lung cancer recurrence, identifying these histone variants as a novel tool for an improved risk stratification of cancer patients. Moreover, macroH2A isoforms are highly expressed in cells undergoing senescence, a known antitumor mechanism, suggesting macroH2A1.1 may be a useful biomarker for senescent cells in tumors.