Background: The International Prognostic Index for patients (pts) with CLL (CLL-IPI) is a validated scoring system with prognostic value for overall survival (OS) in untreated CLL, but it has not been studied in relapsed/refractory (R/R) CLL (Kutsch et al. J Clin Oncol.33 (suppl), 2015). The CLL-IPI is a risk-weighted model comprising the risk factors age (relative weight, 1), stage (1), del(17p)/TP53 mutation (−17p/TP53M) (4), IGHV mutation status (2), and β2-microglobulin (2). We hypothesized that idelalisib (IDELA), an agent active in CLL with −17p/TP53M, can overcome the negative impact of high CLL-IPI risk on OS. Methods: The CLL-IPI score was analyzed in 460 pts with R/R CLL treated with IDELA + rituximab (R) vs placebo + R (NCT01539512) or IDELA + ofatumumab (O) vs O (NCT01659021). Subgroup analyses of OS were performed in 274 pts treated with IDELA + R or + O (IDELA cohort) and in 186 pts treated with R or O alone (control). Median OS was estimated for low, intermediate, high, and very high CLL-IPI risk groups using the Kaplan-Meier method. The log-rank test was used to compare survival distributions across groups and estimate hazard ratios (HRs) for OS. Results: At a median follow-up of 14.7 months, the CLL-IPI score was validated in the pooled cohort of all pts with R/R CLL, with significant differences in OS across CLL-IPI risk groups (P=0.0001; table). In the subgroup analysis, the CLL-IPI score was prognostic for OS in the control (P=0.0007) but not IDELA cohort (P=0.0859). Conclusions: Although low-risk pts are uncommon in the R/R setting, the CLL-IPI score is prognostic of OS in R/R CLL. IDELA partially overcomes the negative impact on OS of very high-risk disease driven by −17p/TP53M. Analyses of data derived from another phase 3 study are ongoing. Clinical trial information: NCT01659021, NCT01539512