OBJECTIVE: To evaluate the long-term effectiveness of laparoscopic sleeve gastrectomy (LSG) in pediatric and transition age patients with Prader-Willi syndrome (PWS). DESIGN: Single-center, longitudinal, retrospective cohort study. METHODS: We reviewed the electronic health records of 110 patients with PWS and 268 subjects undergoing LSG. We included 16 patients with PWS and severe obesity (PWS-LSG) and 32 matched non-syndromic patients with obesity (OB-LSG), both undergoing LSG, and 16 patients with PWS receiving lifestyle intervention only (PWS-LS). The primary endpoint was ΔBMI-SDS% at 5 years. RESULTS: In PWS-LSG, BMI-SDS decreased from 5.18 to an early nadir at 1-2 years (median ΔBMI-SDS% ∼-26%), then partially rebounded to 4.75 at 5 years, with ΔBMI-SDS% -16.9% (P = .012). Conventional metrics confirmed this attenuated response, with %BMI change -2.8% and absolute ΔBMI-SDS -1.10 at 5 years. In OB-LSG, BMI-SDS declined from 4.95 to 2.24, with larger and more sustained improvement (ΔBMI-SDS% -57.4%; P < .001 within-group; P = .002 vs PWS-LSG), corresponding to a %BMI change -40.1% and absolute ΔBMI-SDS -2.81 at 5 years. In PWS-LS, BMI-SDS increased from 2.25 to 3.19 (ΔBMI-SDS% + 36.4%, P = .003). The mean number of obesity-related comorbidities decreased in PWS-LSG (2.69 ± 1.66 to 1.94 ± 1.18; P = .041) and in OB-LSG (1.25 ± 0.88 to 0.56 ± 0.76; P < .001), but increased in PWS-LS (1.56 ± 0.96 to 2.44 ± 1.32; P = .004). CONCLUSION: In PWS, LSG produces clinically relevant early weight loss with partial maintenance at 5 years, but markedly attenuated long-term benefit compared with non-syndromic peers. Nevertheless, when interpreted against the progressive worsening of obesity and cardiometabolic comorbidities observed with lifestyle intervention alone, LSG appears to modify disease trajectory in PWS.