BACKGROUND: There is a lack of evidence on the effectiveness or cost-effectiveness of alternative brands of prosthesis for total knee replacement (TKR). We compared patient-reported outcomes, revision rates, and costs, and estimated the relative cost-effectiveness of five frequently used cemented brands of unconstrained prostheses with fixed bearings (PFC Sigma, AGC Biomet, Nexgen, Genesis 2, and Triathlon). METHODS: We used data from three national databases for patients who had a TKR between 2003 and 2012, to estimate the effect of prosthesis brand on post-operative quality of life (QOL) (EQ-5D-3L) in 53 126 patients at six months. We compared TKR revision rates by brand over 10 years for 239 945 patients. We used a fully probabilistic Markov model to estimate lifetime costs and quality-adjusted life years (QALYs), incremental cost effectiveness ratios (ICERs), and the probability that each prosthesis brand is the most cost effective at alternative thresholds of willingness-to-pay for a QALY gain. FINDINGS: Revision rates were lowest with the Nexgen and PFC Sigma (2.5% after 10 years in 70-year-old women). Average lifetime costs were lowest with the AGC Biomet (£9 538); mean post-operative QOL was highest with the Nexgen, which was the most cost-effective brand across all patient subgroups. For example, for 70-year-old men and women, the ICERs for the Nexgen compared to the AGC Biomet were £2 300 per QALY. At realistic cost per QALY thresholds (£10 000 to £30 000), the probabilities that the Nexgen is the most cost-effective brand are about 98%. These results were robust to alternative modelling assumptions. CONCLUSIONS: AGC Biomet prostheses are the least costly cemented unconstrained fixed brand for TKR but Nexgen prostheses lead to improved patient outcomes, at low additional cost. These results suggest that Nexgen should be considered as a first choice prosthesis for patients with osteoarthritis who require a TKR.