We have previously reported that urinary excretion of serpin-A3 (uSerpA3) is significantly elevated in patients with active lupus nephritis (LN). Here, we evaluated the course of uSerpA3 during the first year of treatment and its association with response to therapy in patients with proliferative LN. The observational longitudinal study included 60 Mexican adults with proliferative LN followed during the first year after LN flare. uSerpA3 was detected by Western blot analysis at flare and after 3, 6, and 12 mo. The response to therapy was determined 1 yr after the LN flare. We evaluated the correlation between uSerpA3 and histological parameters at LN flare. The temporal association between uSerpA3 and response to therapy was analyzed with linear mixed models. uSerpA3 prognostic performance for response was evaluated with receiver-operating characteristic curves. Among the 60 patients studied, 21 patients (35%) were class III and 39 patients (65%) were class IV. uSerpA3 was higher in class IV than in class III LN (6.98 vs. 2.89 dots per in./mg creatinine, P = 0.01). Furthermore, uSerpA3 correlated with the histological activity index (r = 0.29, P = 0.02). There was a significant association between the temporal course of uSerpA3 and response to therapy. Responders showed a significant drop in uSerpA3 at 6 mo compared with LN flare (P < 0.001), whereas nonresponders persisted with elevated uSerpA3. Moreover, uSerpA3 was significantly lower at flare in responders compared with nonresponders (2.69 vs. 6.98 dots per in./mg creatinine, P < 0.05). Furthermore, uSerpA3 was able to identify nonresponders since 3 mo after LN flare (area under the curve: 0.77). In conclusion, uSerpA3 is an early indicator of kidney inflammation and predictor of the clinical response to therapy in patients with proliferative LN.NEW & NOTEWORTHY LN requires aggressive immunosuppression to improve long-term outcomes. Current indicators of remission take several months to normalize, prolonging treatment regiments in some cases. Serpin-A3 is present in urine of patients with proliferative LN. We evaluated the excretion of serpin-A3 in serial samples of patients with proliferative LN during the first year after flare. We found that uSerpA3 correlates with kidney inflammation and its decline at early points predicts the response to therapy 1 yr after flare.