Background: Leg-length inequality is common in the general population and may accelerate development of knee osteoarthritis. Objective: To determine whether leg-length inequality is associated with prevalent, incident, and progressive knee osteoarthritis. Design: Prospective observational cohort study. Setting: Population samples from Birmingham, Alabama, and Iowa City, Iowa. Patients: 3026 participants aged 50 to 79 years with or at high risk for knee osteoarthritis. Measurements: The exposure was leg-length inequality, measured by full-limb radiography. The outcomes were prevalent, incident, and progressive knee osteoarthritis. Radiographic osteoarthritis was defined as Kellgren and Lawrence grade 2 or greater, and symptomatic osteoarthritis was defined as radiographic disease in a consistently painful knee. Results: Compared with leg-length inequality less than 1 cm, leg-length inequality of 1 cm or more was associated with prevalent radiographic (53% vs. 36%; odds ratio [OR], 1.9 [95% CI, 1.5 to 2.4]) and symptomatic (30% vs. 17%; OR, 2.0 [CI, 1.6 to 2.6]) osteoarthritis in the shorter leg, incident symptomatic osteoarthritis in the shorter leg (15% vs. 9%; OR, 1.7 [CI, 1.2 to 2.4]) and the longer leg (13% vs. 9%; OR, 1.5 [CI, 1.0 to 2.1]), and increased odds of progressive osteoarthritis in the shorter leg (29% vs. 24%; OR, 1.3 [CI, 1.0 to 1.7]). Limitations: Duration of follow-up may not be long enough to adequately identify cases of incidence and progression. Measurements of leg length, including radiography, are subject to measurement error, which could result in misclassification. Conclusion: Radiographic leg-length inequality was associated with prevalent, incident symptomatic, and progressive knee osteoarthritis. Leg-length inequality is a potentially modifiable risk factor for knee osteoarthritis. © 2010 American College of Physicians.