Background: Cancer-associated cachexia and weight change from treatment-related side effects profoundly influence treatment outcomes for patients with NSCLC. Limited data are available to compare the association between weight change and OS for patients with NSCLC treated with pembrolizumab alone or combined with chemotherapy. Therefore, we evaluated the change in weight after the first cycle of pembrolizumab-based treatments and its association with OS in patients with metastatic NSCLC. Methods: This retrospective study included 306 patients with NSCLC treated with a first line pembrolizumab-based regimen at Ohio State University from 2018-2021. Baseline characteristics were collected within seven days before cycle one treatment. Percent of weight change (PWC) was calculated as (cycle two weight – baseline weight)/baseline weight x 100%. Severe weight loss was defined as ≥75^th percentile (PWC ≤-3.5%). Kruskal Wallis test was used to compare the significance of median PWC between treatment groups. Cox proportional-hazards models were used to test associations with survival. Results: The median age was 64.0 (IQR 56.7-72.6) years. The median baseline BMI was 26.1 (IQR 22.4-30.7). There was no difference between the median PWCs of patients treated with pembrolizumab monotherapy (-1.2%, IQR -3.7-0.8%) vs. pembrolizumab with chemotherapy (-1.0%, IQR -3.4-0.6%), p = 0.587. The patients whose weight remained stable (PWC -1% to 1%, n = 87 (28.4%)) had the highest median OS at 45.6 months (95% CI 27.6 – not reached); while those with severe weight loss (PWC ≤-3.5%, n = 78 (25.5%)) and weight gain (PWC ≥1%, n = 65 (21.2%)) had significantly decreased survival with median OS 15.6 (95% CI 9.3-20.9) and 16.3 (95% CI 10.1-25.6) months respectively, overall model p-value < 0.001. The PWC remained significantly associated with OS after adjusting for performance status, PD-L1, and treatment with p < 0.001 (Table 1). Conclusions: For patients with metastatic NSCLC treated with first line pembrolizumab-based regimen, similar PWCs were seen between patients treated with pembrolizumab alone or combined with chemotherapy. Regardless of treatment, weight gain and severe weight loss after the first cycle of treatment were associated with reduced OS. Further in-depth analysis is warranted to investigate the potential causes of weight changes, especially for patients with positive PWC.