Background: A small proportion of non-small cell lung cancers (NSCLCs) have been observed to spread to distant lymph nodes (N3) or metastasize (M1) or both, while the primary tumor is small (≤3 cm, T1). These small aggressive NSCLCs (SANSLSC) are important as they are clinically significant, may identify unique biologic pathways, and warrant aggressive follow-up and treatment. This study identifies factors associated with SA-NSCLC and attempts to validate a previous finding that women with a family history of lung cancer are at particularly elevated risk of SA-NSCLC. Methods: This study used a case-case design within the National Cancer Institute's National Lung Screening Trial (NLST) cohort. Case patients and "control" patients were selected based on TNM staging parameters. Case patients (n=64) had T1 NSCLCs that were N3 or M1 or both, while "control" patients (n=206) had T2 or T3, N0 to N2, and M0 NSCLCs. Univariate and multivariable logistic regression were used to identify factors associated with SA-NSCLC. Results: In bootstrap bias-corrected multivariable logistic regression models, small aggressive adenocarcinomas were associated with a positive history of emphysema (odds ratio [OR] = 5.15, 95% confidence interval [CI] = 1.63 to 23.00) and the interaction of female sex and a positive family history of lung cancer (OR=6.55, 95% CI=1.06 to 50.80). Conclusions: Emphysema may play a role in early lung cancer progression. Females with a family history of lung cancer are at increased risk of having small aggressive lung adenocarcinomas. These results validate previous findings and encourage research on the role of female hormones interacting with family history and genetic factors in lung carcinogenesis and progression.