Central nervous system (CNS) relapse following R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) occurs in 2–5% of patents with diffuse large B‐cell lymphoma (DLBCL). Many patients aged ≥70 years are unsuitable for high‐dose methotrexate (HDMTX) prophylaxis and therefore often receive stand‐alone intrathecal prophylaxis. The CNS international prognostic index (CNS‐IPI) is a clinical CNS relapse risk score that has not specifically been validated in elderly patients. The value of CNS prophylaxis in patients aged ≥70 years remains uncertain. Data on 690 consecutively R‐CHOP‐treated DLBCL patients aged ≥70 years were collected across 8 UK centres (2009–2018). CNS prophylaxis was administered per physician preference. Median age was 77·2 years and median follow‐up was 2·8 years. CNS‐IPI was 1–3 in 60·1%, 4 in 23·8%, 5 in 13·0% and 6 in 3·3%. Renal and/or adrenal (R/A) involvement occurred in 8·8%. Two‐year overall CNS relapse incidence was 2·6% and according to CNS‐IPI, 1–3:0·8%, 4:3·6%, 5:3·8% and 6:21·8%. Two‐year CNS relapse incidence for R/A was 10·0%. When excluding HDMTX (n = 31) patients, there remained no change in unadjusted/adjusted CNS relapse for intrathecal prophylaxis effect according to CNS‐IPI. CNS‐IPI is valid in elderly R‐CHOP‐treated DLBCL patients, with the highest risk in those with CNS‐IPI 6 and R/A involvement. We observed no clear benefit for stand‐alone intrathecal prophylaxis but observed an independent increased risk of infection‐related admission during R‐CHOP when intrathecal prophylaxis was administered.