PURPOSE: To estimate the downstream effect of septic first revision total knee arthroplasty (rTKA) on the risk of second and third revision compared with aseptic first rTKA. METHODS: A register study of The Danish National Patient Registry and The Danish Knee Arthroplasty Register. rTKAs performed in Denmark from 1998 to 2021 were identified. We included only major revisions defined as the exchange of the tibial and/or femoral components and isolated liner exchanges or patella revisions were not included. Two-stage revisions were counted as one revision. The exposure group was defined as revisions due to any septic indication (Group 1) while the control group was revisions due to all aseptic indications (Group 2). Cox regression analysis was used to compare the groups and estimate the hazard ratio with 95% confidence interval (95% CI) for revision. RESULTS: We identified 1016 septic first revisions in Group 1 and 3902 aseptic first revisions in Group 2. The adjusted cox regression analysis demonstrated that Group 1 had a greater risk of a second revision compared to Group 2 (HR 1.4 [95% CI 1.2-1.7]). Additionally, Group 1 had a greater risk of a third revision compared to Group 2 (adjusted HR 1.6 [95% CI 1.1-2.3]). CONCLUSIONS: This is the first study to investigate the downstream risk of revision after a first revision TKA. The adjusted HR of the risk of a third revision was 1.6 higher for septic first rTKAs compared to aseptic first rTKAs, not counting insertions of spacers. This prolonged consequence of PJI is important information for both surgeons and patients. LEVEL OF EVIDENCE: Level III, retrospective comparative study.