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OBJECTIVE: Long-term azithromycin treatment effectively prevents acute exacerbations of chronic obstructive pulmonary disease (COPD). However, patients would benefit from better identification of responders and non-responders to minimise unnecessary exposure. We aimed to assess treatment effect heterogeneity and estimate individual treatment effects (ITEs) to distinguish patients most likely to benefit from prophylactic treatment. METHODS: We used data from 1025 patients of the MACRO trial to assess the ITE of azithromycin on annual exacerbation rate. A Causal Forest was used as a causal machine learning model. We independently validated our findings using data from 83 patients of the COLUMBUS trial. RESULTS: The tertile of patients with the best predicted ITE within MACRO and within the COLUMBUS independent validation cohort showed significant and substantially greater reductions in annual exacerbation rates (in MACRO -0.50, rate ratio 0.70, p=0.01, in COLUMBUS: -2.28, rate ratio 0.43, p<0.001) compared with the average treatment effect across the entire cohort (MACRO -0.35, rate ratio 0.83, p=0.01 and COLUMBUS -1.28, rate ratio 0.58, p=0.001). Conversely, no significant treatment effect was observed in the remaining two-thirds of patients. Primary determinants of ITE included respiratory symptoms, white blood cell count, haemoglobin, C-reactive protein and forced vital capacity. Smoking status did not emerge as a significant predictor. CONCLUSION: Based on five easily obtainable parameters to predict ITE, we identified treatment effect heterogeneity in COPD subjects treated with azithromycin maintenance therapy and found a small subgroup of responders driving the average reduction in exacerbations reported in previous trials.