Patients with osteoarthritis undergoing knee replacement have been reported to have an overall reduced mortality compared with that of the general population. This has been attributed to the selection of healthier patients for surgery. However, previous studies have had a maximum follow-up time of ten years. We have used information from the Swedish Knee Arthroplasty Register to study the mortality of a large national series of patients with total knee replacement for up to 28 years after surgery and compared their mortality with that of the normal population. In addition, for a subgroup of patients operated on between 1980 and 2002 we analysed their registered causes of death to determine if they differed from those expected. We found a reduced overall mortality during the first 12 post-operative years after which it increased and became significantly higher than that of the general population. Age-specific analysis indicated an inverse correlation between age and mortality, where the younger the patients were, the higher their mortality. The shift at 12 years was caused by a relative over-representation of younger patients with a longer follow-up. Analysis of specific causes of death showed a higher mortality for cardiovascular, gastrointestinal and urogenital diseases. The observation that early onset of osteoarthritis of the knee which has been treated by total knee replacement is linked to an increased mortality should be a reason for increased general awareness of health problems in these patients.