- There is evidence that Hodgkin Reed-Sternberg (HRS) cells in classical Hodgkin's lymphoma (cHL) could display some molecular and morphological markers of cellular senescence (CS). We hypothesized that CS mechanisms may have potential prognostic relevance in cHL and investigated whether the expression of the well-established CS biomarkers p21CIP1/WAF1 and p16INK4a by HRS cells might be predictive of the probability of event-free survival (EFS). The study analyzed a retrospective cohort of 147 patients and the results were validated on a cohort of 91 patients independently diagnosed and treated in a different institution. p16INK4a and p21CIP1/WAF1 were categorized as dichotomous variables (< or ≥ 30% of HRS cells at diagnosis) and evaluated in univariate and multivariate analysis. Both molecules were independent prognostic factors. A positive staining of one of the two molecules in more than 30% HRS cells predicted a better EFS (p<0.01). p16INK4a/p21CIP1/WAF1 together as a unique categorical variable (both <30%, either <30%, both ≥ 30%) sorted out three prognostic groups with better, intermediate or worse outcome either overall or within I-II, bulky and advanced stages. The presence or the lack of the robust expression of p21CIP1/WAF1 and/or p16INK4a defined the prognosis in our series. These findings point to (i) the relevance of cellular senescence-related mechanisms in cHL, and to (ii) the prognostic value of a simple, reproducible and low-cost immunohistochemical evaluation of p16INK4a and p21CIP1/WAF1 expression. Copyright © 2015, American Association for Cancer Research.