Purpose <p>Smoking history and age are established lung cancer risk factors incorporated into screening guidelines. Social vulnerability index (SVI), a social determinant of health, has also been associated with cancer risk. We investigated the association between SVI and malignancy in high-risk, screen-detected pulmonary nodules.</p> Methods <p>Patients with lung-RADS 4A, 4B, or 4X nodules identified on low-dose computed tomography screening at a single institution (2015–2024) were included. Non-Illinois residents, patients with incomplete address data, loss to follow-up, or declined evaluation were excluded. Malignancy was confirmed through clinical assessment, staging, and positron emission tomography imaging. SVI was determined by geocoding patient addresses to census tracts and applying the CDC tract-level SVI calculator. Logistic regression assessed associations between SVI and malignancy, including interaction models evaluating whether the association varied by dominant nodule size. Youden’s analysis identified the optimal SVI cutpoint.</p> Results <p>Among 398 patients, 50% were male and 56% White. Median age was 67&#xa0;years (IQR 63–72), smoking history 40 pack-years (IQR 30–50), nodule size 1.1&#xa0;cm (IQR 0.8–1.5), and SVI 0.62 (IQR 0.31–0.83). Malignancy was diagnosed in 36% (144/398). Receiver operating characteristic analysis identified an optimal SVI cutpoint of 0.50 with 68% sensitivity for malignancy. On multivariable analysis, SVI ≥ 0.50 was associated with increased odds of malignancy (OR 1.56, 95% CI 1.01–2.42, <i>p</i> = 0.046). Significant interactions between SVI and nodule size were observed for continuous SVI (OR 4.08, 95% CI 1.49–11.18, <i>p</i> = 0.006) and binary SVI ≥ 0.50 (OR 1.93, 955 CI 1.10–3.39, <i>p</i> = 0.022).</p> Conclusion <p>Higher SVI was associated with malignant pulmonary nodules, particularly in smaller or indeterminate nodules.</p>