Rationale: Rheumatoid arthritis (RA) has been implicated in interstitial lung disease, as the majority of studies have comprised patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples. Objective: We sought to determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILAs) on computed tomography scans. Methods: Associations of RA-risk HLA-DRB1 alleles (*04:01, *04:08, *04:05, *04:04, and *10:01) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 4,018) and COPDGene (n = 5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry. Results: The prevalence of an RA-risk HLA-DRB1 allele was 16.5% and 21.9% in the MESA and COPDGene cohorts, respectively. ILA was present in 3.9% and 11% of the MESA and COPDGene cohorts, respectively. An RA-risk HLA-DRB1 allele was not significantly associated with ILA in the MESA and COPDGene cohorts. In the MESA cohort, higher serum levels of immunoglobulin (Ig)A rheumatoid factor (RF) and anticyclic citrullinated peptide were associated with odds ratios for ILA of 1.20 (95% confidence interval [CI] = 1.07-1.35) and 1.19 (95% CI = 1.04-1.38), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an odds ratio for ILA 10 years later of 1.25 (95% CI = 1.08-1.44). Associations were not significantly different by MUC5B risk allele status. Conclusions: RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.