© 2016, American College of Rheumatology Objective: To examine neuromuscular factors that predict the incidence and progression of knee instability symptoms in older adults with or at high risk of knee osteoarthritis (OA). Methods: At the 60-month clinic visit, participants in the Multicenter Osteoarthritis Study underwent evaluation of quantitative vibratory sense at the knee and isokinetic quadriceps muscle strength. At this 60-month visit, participants were also asked about knee buckling and sensations of knee shifting or slipping without buckling in the past 3 months and then were asked the same questions at the 72- and 84-month follow-up visits. We performed a person-based analysis using Poisson regression analysis with robust error variance to estimate adjusted relative risks (RRs) for the association of vibratory sense and muscle strength with the incidence and worsening of knee slipping/shifting, buckling, and overall knee instability symptoms (either buckling or knee shifting/slipping), with adjustment for relevant confounders. Results: A total of 1,803 participants (61% women) were included. Approximately one-third of the participants reported incident or worsening of instability symptoms over the study period. After adjustment for relevant confounders, better vibratory acuity (adjusted RR 0.78, 95% confidence interval [95% CI] 0.56–1.09), P = 0.020 for trend) and greater quadriceps strength (adjusted RR 0.53, 95% CI 0.38–0.75, P < 0.001) protected against incident knee instability symptoms. Greater quadriceps strength (adjusted RR 0.73, 95% CI 0.58–0.92, P = 0.008) also protected against worsening of knee instability symptoms. Conclusion: Vibratory acuity and quadriceps muscle strength are important predictors of the incidence and worsening of knee instability over 2 years. These neuromuscular factors are potentially modifiable and should be considered in interventional studies of instability in persons with or at risk of knee OA.