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Objectives To evaluate the diagnostic and prognostic value of serum Krebs von den Lungen-6 (KL-6) and interleukin-18 (IL-18) in detecting interstitial lung disease (ILD) and predicting disease progression and mortality in patients with systemic sclerosis (SSc) over a 24-month period.Design Prospective longitudinal cohort study.Setting Single-centre tertiary referral unit for systemic autoimmune diseases.Participants 74 patients fulfilling classification criteria for SSc were included and stratified according to ILD status based on high-resolution CT (HRCT).Interventions Participants underwent serial clinical assessments, pulmonary function tests and serum biomarker measurements (KL-6, IL-18 and IL-18 binding protein) at baseline, 12 months and 24 months.Main outcome measures Presence and severity of ILD on HRCT, ILD progression (defined by decline in forced vital capacity (FVC) and radiological worsening using the modified Goh score) and all-cause mortality.Results At baseline, 38% of patients had ILD, increasing to 54% at 24 months. The proportion with ≥20% lung involvement rose from 32% to 43%, and extensive disease increased from 11% to 25% (p=0.03). Serum KL-6 and IL-18 levels were significantly higher in patients with SSc-ILD and correlated inversely with % Forced Vital Capacity (%FVC) (r=−0.51, p=0.0007) and %DLCO (r=−0.38, p=0.001). Longitudinal increases in KL-6 were associated with lung function decline and HRCT progression. An annual increase of +14.18 U/mL predicted progressive ILD (area under the curve (AUC) 0.803, p=0.002; sensitivity 80%, specificity 64%). For mortality, an annual increase of +71.17 U/mL demonstrated high predictive accuracy (AUC 0.91, 95% CI 0.84 to 0.99, p<0.0001; sensitivity 75%, specificity 85%). A decline in diffusing capacity for carbon monoxide (DLCO) of −17% per year was also associated with mortality. In multivariable analysis, changes in KL-6, DLCO, C-reactive protein and anti-Scl-70 positivity independently predicted ILD progression, while immunosuppressive therapy was protective (OR 0.27, 95% CI 0.16 to 0.92, p=0.004).Conclusions Serum KL-6 and IL-18 are valuable diagnostic and prognostic biomarkers in SSc-ILD. Baseline levels reflect disease presence and severity, while longitudinal changes in KL-6 provide robust prediction of progression and mortality. These findings support their integration into routine clinical practice for risk stratification and disease monitoring.