BACKGROUND: Loading and contraction failure (muscular exhaustion) are strength training variables known to influence neural activation of the exercising muscle in healthy subjects, which may help reduce neural inhibition of the quadriceps muscle following total knee arthroplasty (TKA). It is unknown how these exercise variables influence knee pain after TKA. OBJECTIVE: To investigate the effect of loading and contraction failure on knee pain during strength training, shortly following TKA. DESIGN: Cross-sectional study. SETTING: Consecutive sample of patients from the Copenhagen area, Denmark, receiving a TKA, between November 2012 and April 2013. PARTICIPANTS: Seventeen patients, no more than 3 weeks after their TKA. MAIN OUTCOME MEASURES: In a randomized order, the patients performed 1 set of 4 standardized knee extensions, using relative loads of 8, 14, and 20 repetition maximum (RM), and ended with 1 single set to contraction failure (14 RM load). The individual loadings (kilograms) were determined during a familiarization session >72 hours prior. The patients rated their knee pain during each repetition, using a numerical rating scale (0-10). RESULTS: Two patients were lost to follow up. Knee pain increased with increasing load (20 RM: 3.1±2.0 points, 14 RM: 3.5±1.8 points, 8 RM: 4.3±2.5 points, P = 0.006), and repetitions to contraction failure (10% failure: 3.2±1.9 points, 100% failure: 5.4±1.6 points, P<0.001). Resting knee pain 60 seconds after the final repetition (2.7±2.4 points) was not different from that recorded before strength training (2.7±1.8 points, P = 0.88). CONCLUSION: Both loading and repetitions performed to contraction failure during knee- extension strength-training, increased post-operative knee pain during strength training implemented shortly following TKA. However, only the increase in pain during repetitions to contraction failure exceeded that defined as clinically relevant, and was very short-lived. TRIAL REGISTRATION: ClinicalTrials.gov NCT01729520.