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BACKGROUND: Effects of sedentary behavior across the spectrum of future disease, including cardiovascular-kidney-metabolic (CKM) syndrome-related conditions, are poorly understood.OBJECTIVES: The objective of the study was to examine associations between accelerometer-measured sedentary behavior and incidence of >700 conditions.METHODS: Among UK Biobank participants with accelerometer-measured sedentary time, we fit multivariable-adjusted Cox models with P value thresholds targeting a false discovery rate of 1%. To estimate the impact of sedentary behavior on population-level disease burden, we calculated population-attributable fractions (PAFs) for key CKM conditions and compared them to the American Heart Association Life's Essential 8.RESULTS: Among 89,537 individuals (age 63 ± 8 years, 56.3% women) undergoing accelerometry with a median follow-up 8.0 years (quartile-1: 7.5, quartile-3: 8.5), sedentary time was associated with 81/761 (10.6%) incident diseases at false discovery rate 1%. Seventy-five associations (92.6%) indicated higher disease risk with greater sedentary time. Strongest associations were observed for CKM conditions, where using the second quartile (8.2-9.4 hours/day) as a referent, sedentary time in the top quartile (>10.6 hours/day) was associated with substantially higher risks of hypertension (HR: 1.13; 95% CI: 1.08-1.19), diabetes (HR: 1.18; 95% CI: 1.07-1.31), chronic kidney disease (HR: 1.14; 95% CI: 1.02-1.27), and obstructive sleep apnea (HR: 1.19; 95% CI: 0.99-1.42). At the >10.6 hours/day threshold, excess sedentary behavior was associated with population-level risks of hypertension (PAF: 1.6%; 95% CI: 1.2-1.9), diabetes (PAF: 1.3%; 0.5-2.7), chronic kidney disease (PAF: 1.9%; 1.2-2.5) and obstructive sleep apnea (PAF: 4.2%; 2.3-6.6) exceeding certain components of Life's Essential 8 (eg, adequate sleep).CONCLUSIONS: Excess sedentary behavior is broadly associated with future disease risk. Effects are prominent for CKM conditions, where population-level burden rivals consensus lifestyle factors. Avoiding excess sedentary behavior should be a key public health target.