Background: Maintenance of weight loss after a diet and exercise intervention is often low. Moreover, short follow-up periods and high attrition rates often impede translation of study results to clinical practice. Objective: The present study evaluated the long-term effectiveness of a randomized, tailor-made lifestyle intervention, consisting of diet and exercise, on the health and lifestyle of overweight, middleaged women in primary care. Design: The intervention was part of a randomized controlled trial on the prevention of knee osteoarthritis [PROOF (PRevention of knee Osteoarthritis in Overweight Females) study]. The intervention lasted 2.5 y and consisted of visits to the dietitian and participation in physical activity classes, supervised by a physiotherapist. The outcome of main interest of the present study was weight change (in kg) 6-7 y after randomization. Additionally, the intervention's effect on change in physical activity was investigated. Results: After 6 mo, weight loss was significantly higher in the intervention group (adjusted difference: 1.34 kg; 95% CI: 0.46, 2.22 kg). Over time, this difference decreased and became nonsignificant after 24 mo. Per-protocol analyses showed similar results. After 6 mo, change in physical activity was significantly higher in the intervention group (15.2%; 95% CI: 28.6%, 1.7%). Over time, this difference increased up to 29.8% (95% CI: 2.3%, 57.2%) after 6.6 y of follow-up. Per-protocol analyses showed no significant differences in change in physical activity. Conclusions: A long-lasting intervention effect on change in physical activity was found, which increased over time. For weight change, smaller differences were found, which decreased over time. In future research, greater intervention effects on weight change are expected when higher compliance rates can be reached. The present study provides important recommendations for future research.