Objective: To describe the natural history of patellofemoral (PF) joint bone marrow lesions (BMLs) over 2.6 years and associations between changes in PF joint BMLs, knee pain, and knee cartilage morphology in older adults over 5 years. Methods: A prospective population-based cohort study of men and women ages 50–80 years (mean age 63 years, n = 406) was performed. PF joint BMLs, knee cartilage volume, and cartilage defect scores (range 0–4) were measured using the Whole-Organ Magnetic Resonance Imaging Score system at baseline and at 2.6 years. Knee pain was assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at baseline and at 5 years. Results: At baseline, 27% (n = 109) had PF joint BMLs; 24% of these increased (WOMAC score change of ≥1) at followup, 44% persisted, 32% decreased, and 21% resolved completely. Of those without PF joint BMLs at baseline, 20% of participants developed PF joint BMLs over 2.6 years. In multivariable analyses, a change in PF joint BMLs was deleteriously associated with a change in total knee pain (β = 0.67, 95% confidence interval [95% CI] 0.03, 1.31) and knee pain when going up/down stairs (β = 0.24, 95% CI 0.04, 0.44) over 5 years. Baseline PF joint and tibiofemoral joint cartilage volume were protective for PF joint BMLs (relative risk [RR] 0.69, 95% CI 0.52, 0.90 for PF joint), while baseline PF joint cartilage defects were associated with an increase in PF joint BMLs (RR 1.73, 95% CI 1.38, 2.17) over 2.6 years. TF joint cartilage defects were not associated with increases in PF joint BMLs. Conclusion: PF joint BMLs are not static, and change is clinically relevant. PF joint cartilage morphology predicts increases in PF joint BMLs.