Background <p>There is currently a lack of noninvasive biomarkers that effectively predict the progression of IgA nephropathy. We investigated the value of urinary IL-18 in predicting the progression of IgA nephropathy and whether its combination with clinical variables improved risk prediction.</p> Methods <p>A total of 136 patients with IgA nephropathy were followed up for a median of 36 months in four academic medical centers. The levels of three biomarkers, urinary IL-18, urinary KIM-1 and urinary NGAL, were measured via ELISA in patients with 136 IgA nephropathy. The progression of IgA nephropathy was defined as a &gt; 50% decrease in the eGFR or end-stage kidney disease. Multivariate Cox regression analyses of urine biomarkers for predicting the progression of IgA nephropathy were performed, and the AUCs of the clinical prediction models were calculated.</p> Results <p>Kaplan–Meier analysis revealed that high levels (&gt; 28.1 pg/mg of creatinine) of urinary IL-18 were associated with a significantly poor renal outcome (<i>P</i> &lt; 0.01), and Cox analysis further confirmed this result. High levels of urinary IL-18 were associated with a 4.7-fold greater risk for IgA nephropathy progression in adjusted analyses. For predicting IgA nephropathy progression, urinary IL-18 yielded a C-statistic of 0.77 (95% CI, 0.67–0.86), renal injury molecule 1 yielded 0.75 (95% CI, 0.65–0.86), and uNGAL yielded 0.70 (95% CI, 0.59–0.80). Urinary IL-18 levels significantly improved the C statistic from 0.77 to 0.89, outperforming the clinical and MEST-C scores.</p> Conclusion <p>Urinary IL-18 is a significant predictor of poor renal outcomes and improves the risk prediction of IgA nephropathy.</p>