OBJECTIVES: The present study investigated (1) trends in the prevalence and incidence of knee osteoarthritis over a 20-year period (1996-2015); (2) trends in multimorbidity and (3) trends in drug prescriptions. DESIGN: Registry-based study. SETTING: Primary healthcare, Flanders, Belgium. PARTICIPANTS: Data were collected from Intego, a general practice-based morbidity registration network. In the study period between 1996 and 2015, data from 440 140 unique patients were available. OUTCOME MEASURES: Trends in prevalence and incidence rate of knee osteoarthritis were computed using joinpoint regression analysis. The mean disease count was calculated to assess trends in multimorbidity. In addition, the number of drug prescriptions was identified by the Anatomical Therapeutic Chemical Classification code and trends were equally recorded with joinpoint regression. RESULTS: The total age-standardised prevalence of knee osteoarthritis increased from 2.0% in 1996 to 3.6% in 2015. An upward trend was observed with an average annual percentage change (AAPC) of 2.5 (95% CI 2.2 to 2.9). In 2015, the prevalence rates in the 10 year age groups from the 45-54 years age group onwards were 3.1%, 5.6%, 9.0% and 13.9%, to reach 15.0% in people aged 85 years and older. The incidence remained stable with 3.75‰ in 2015 (AAPC=-0.5, 95% CI -1.4 to 0.5). The mean disease count significantly increased from 1.63 to 2.34 (p<0.001) for incident cases with knee osteoarthritis. Finally, we observed a significantly positive trend in the overall prescription of acetaminophen (AAPC=6.7, 95% CI 5.6 to 7.7), weak opioids (AAPC=4.0, 95% CI 0.9 to 7.3) and glucosamine (AAPC=8.6, 95% CI 2.4 to 15.1). Oral non-steroidal anti-inflammatory drugs were most prescribed, with a prevalence rate of 29.8% in 2015, but remained stable during the study period (AAPC=0.0, 95% CI -1.1 to 1.1). CONCLUSIONS: Increased prevalence, multimorbidity, and number of drug prescriptions confirm an increased burden of knee osteoarthritis. In future, these trends can be ...