The aim of the study was to identify specific clinical and serum protein biomarkers that are associated with longitudinal outcome of RA-associated interstitial lung disease (RA-ILD). 60 RA patients with clinical and serological profiles were assessed by HRCT and pulmonary function tests (PFTs) at baseline (Year 0) and 5 years post enrollment (Year 5). Progression versus non-progression was defined based on changes in Quantitative Modified HRCT scores and PFTs over time. Specific serum protein biomarkers were assessed in serum samples at baseline and Year 5 by Multiplex enzyme-linked immunosorbent assays (ELISAs). At Year 5, 32% of patients demonstrated progressive RA-ILD, 35% were stable, and 33% improved. Baseline age and rheumatoid factor (RF) were significantly different between RA-ILD outcomes of progression vs. no-progression (p < 0.05). Changes in levels of CXCL11/I-TAC and MMP13 over 5 years also distinguished pulmonary outcomes (p < 0.05). A final binary logistic regression model revealed that baseline age and changes in serum MMP13 as well as CXCL11/I-TAC were associated with RA-ILD progression at Year 5 (p < 0.01), with an AUC of 0.7772. Collectively, these analyses demonstrated that baseline clinical variables (age, RF) and shifts in levels of selected serum proteins (CXCL11/I-TAC, MMP13) were strongly linked to RA-ILD outcome over time.