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Objectives: While the effect of physical activity on knee osteoarthritis (KOA) remains controversial, how sitting and sleep durations affect KOA is unknown. We evaluated the association between durations of physical activity, sitting and sleep, and incidence of total knee replacement (TKR) due to severe KOA., Methods: We used data from the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese, aged 45-74 years at recruitment from 1993-1998. Height, weight, lifestyle factors, hours of sitting and sleep per day, and hours of moderate activity, strenuous sports or vigorous work per week were assessed through in-person interviews using structured questionnaires. Incident cases of TKR were identified via record linkage with nationwide hospital discharge database., Results: Compared to those with <0.5 hour/week of moderate physical activity, participants with ≥5 hour/week had increased risk of TKR risk [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.00-1.35]. Conversely, duration of sitting activities, especially sitting at work, was associated with reduced risk in a stepwise manner. Compared to <4 hour/day of sitting, those with ≥12 hour/day had the lowest risk (HR 0.76, 95% CI 0.60-0.96, p for trend = 0.02). Sleep duration was inversely associated with reduced risk of TKR in a dose-dependent manner; compared to those with sleep ≤ 5 hour/day, participants with ≥ 9 hour/day had the lowest risk (HR 0.55, 95% CI) 0.43-0.70, p for trend <0.001)., Conclusion: While prolonged sitting or sleeping duration could be associated with reduced risk of severe KOA, extended duration of physical activity could be associated with increased risk., Competing Interests: The authors have declared that no competing interests exist.