The study objective was to determine whether the clinical response of older adults with knee osteoarthritis and overweight or obesity to 18 months of diet and exercise or attention control interventions differed between participants from rural versus urban communities. Participants were 823 older adults (mean age, 64.6 years; 77% women) with knee osteoarthritis, overweight or obesity, who resided in rural (N = 410) and urban (N = 413) counties in North Carolina. All were enrolled in the WE-CAN clinical trial that randomly assigned participants to either 18-months of diet and exercise (D+E) or attention control (C) interventions. General linear models were used to examine differences in clinical outcomes between rural and urban groups after adjusting for covariates. The rural group had significant differences (P<.05) at baseline in clinical outcomes, education, comorbidities, medication use, and income compared to the urban dwellers. After adjusting for baseline differences, the group (rural, urban) by treatment (D+E, C) interactions for WOMAC pain (rural: D+E-C= -0.63,95%CI,-1.31 to 0.06; urban: D+E-C= -0.29,95%CI,-0.99 to 0.41;P=.50) and WOMAC function (rural: D+E-C = -4.60,95%CI,-6.89 to -2.31; urban: D+E-C = -1.38,95%CI,-3.73 to 0.94;P=.054) indicated that the groups responded similarly to the interventions. Among participants with knee osteoarthritis and overweight or obesity, diet and exercise compared to attention control led to similar pain outcomes in rural and urban dwellers that favored diet and exercise; the possibility there may be greater differential efficacy in functional outcomes among rural participants needs further study.