OBJECTIVE: To develop and validate a prognostic model to predict deterioration in health-related quality of life (dHRQoL) in older general practice patients with at least one chronic condition and one chronic prescription. STUDY DESIGN AND SETTING: We used individual participant data from five cluster-randomized trials conducted in the Netherlands and Germany to predict dHRQoL, defined as a decrease in EQ-5D-3L index score of =5 % after six-month follow-up in logistic regression models with stratified intercepts to account for between-study heterogeneity. The model was validated internally, and by using internal-external cross-validation (IECV). RESULTS: - In 3,582 patients with complete data, of whom 1,046 (29.2 %) showed deterioration in HRQoL, 12/87 variables were selected that were related to single (chronic) conditions, inappropriate medication, medication underuse, functional status, well-being and HRQoL. Bootstrap internal validation showed a C-statistic of 0.71 (0.69 to 0.72), and a calibration slope of 0.88 (0.78 to 0.98). In the IECV loop, the model provided a pooled C-statistic of 0.68 (0.65 to 0.70) and calibration-in-the-large of 0 (-0.13 to 0.13). HRQoL/functionality had the strongest prognostic value. CONCLUSION: - The model performed well in terms of discrimination, calibration, and generalizability and might help clinicians identify older patients at high-risk of dHRQoL. REGISTRATION: PROSPERO ID: CRD42018088129.