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Background: The introduction of the novel therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI) has been effective in improving weight gain in both clinical trials and real-world studies. However, the magnitude of this effect appears to be heterogeneous across patient subgroups. This study aims to identify potential determinants of heterogeneity in weight gain following 6-month ETI therapy. Methods: We conducted a multicenter, prospective cohort study enrolling 92 adults with CF at two major CF centers in Italy with follow-up visit at one month and six months from ETI initiation. The treatment's effect on weight changes was evaluated using mixed effect regression models that included subject-specific random intercepts and fixed effects for potential predictors of treatment response, time and a predictor-by-time interaction term. Results: The mean weight gain at six months from the start of treatment was 4.6 kg (95% CI: 2.3–6.9) for the 10 patients with underweight, 3.2 kg (95% CI: 2.3-4.0) for the 72 patients with normal weight, and 0.7 kg (95% CI: -1.6-3.0) for the 10 patients with overweight. After six months of ETI treatment, 8 (80%) of the patients with underweight transitioned to the normal weight category, while 11 (15.3%) of the normal-weight patients became overweight. The major determinants of heterogeneity in weight gain were the baseline BMI and the presence of at least one CFTR residual function mutation, explaining 13% and 8% of the variability, respectively. Conclusions: Our results indicate that ETI is highly effective in improving weight gain in underweight subjects with CF. However, our data also suggests the need for close monitoring of excess weight gain to prevent potential cardiometabolic complications. Highlights: We reported heterogeneity in weight gain after 6 months of treatment with ETI. Baseline BMI and CFTR genotype predict heterogeneity in treatment response. People with underweight received the greatest benefit from ETI treatment. An amount of 15% of normal-weight subjects became overweight. [ABSTRACT FROM AUTHOR]