Background <p>Water vapor thermal therapy (WVTT) determines the injection strategy primarily according to prostatic urethral length. However, no quantitative indicator integrates prostate size and injection number. This study evaluated the association between volume per injection (VPI), defined as prostate volume divided by the number of injections, and treatment failure after WVTT.</p> Methods <p>This retrospective study included 105 consecutive patients who received WVTT. Treatment failure represented the first occurrence of medication resumption, re-catheterization, or re-surgery. The Cox proportional hazards models were used to assess the association between continuous VPI and treatment failure. A multivariable model including the use of 5-alpha reductase inhibitor (5-ARI) was utilized in the sensitivity analysis.</p> Results <p>During a median follow-up of 455 (95% confidence interval [CI]: 377–538) days, 15 patients experienced treatment failure. A higher VPI was associated with an increased risk of treatment failure in the univariate analysis (hazard ratio per 1-mL increase: 1.21, 95% CI: 1.03–1.42, <i>p</i> = 0.020). The association remained significant after adjusting for the use of 5-ARI (hazard ratio: 1.23, 95% CI: 1.04–1.45, <i>p</i> = 0.018).</p> Conclusions <p>A higher VPI was associated with an increased risk of treatment failure after WVTT for BPH. These findings suggest a potential relationship between injection density relative to prostate size and treatment durability. However, given the exploratory nature of the study and the limited number of events, the results should be interpreted with caution. Further prospective validation is warranted.</p>