Background The relation of knee replacement (KR) surgery to all-cause mortality has not been well established owing to potential biases in previous studies. Thus, we aimed to examine the relation of KR to mortality risk among patients with knee osteoarthritis (OA) focusing on identifying biases that may threaten the validity of prior studies.

Methods We included knee OA subjects (ages 50–89 years) from The Health Improvement Network, an electronic medical records database in the UK. Risk of mortality among KR subjects was compared with propensity score-matched non-KR subjects. To explore residual confounding bias, subgroup analyses stratified by age and propensity scores were performed.

Results Subjects with KR had 28% lower risk of mortality than non-KR subjects (HR 0.72, 95% CI 0.66 to 0.78). However, when stratified by age, protective effect was noted only in older age groups (>63 years) but not in younger subjects (≤63 years). Further, the mortality rate among KR subjects decreased as candidacy (propensity score) for KR increased among subjects with KR, but no such consistent trend was noted among non-KR subjects.

Conclusions While a protective effect of KR on mortality cannot be ruled out, findings of lower mortality among older KR subjects and those with higher propensity scores suggest that prognosis-based selection for KR may lead to intractable confounding by indication; hence, the protective effect of KR on all-cause mortality may be overestimated.