Purpose Existing literature lacks an analysis of factors predicting the achievement of minimum clinically important differences (MCID) after water vapor thermal therapy (WVTT) for prostatic hyperplasia. This study aims to identify these predictors over a 36-month post-WVTT period. Methods This prospective single surgeon case series assessed male patients receiving WVTT. Eligibility criteria included being at least 45 years old, having an estimated prostate volume (EPV) of 30-80 cc, an International Prostate Symptom Score (IPSS) of 12 points or more, and a maximum urinary flow rate (Qmax) under 16 mL/sec. MCID, representing the smallest symptomatic improvement perceived by patients, was calculated using the distribution-based method, considering half a standard deviation of baseline IPSS scores. Correlation and linear regression analyses assessed MCID attainment. Multivariable logistic regression evaluated MCID achievement, considering multicollinearity, heteroskedasticity, and normality. Results Of 206 men with a median 29.1-month follow-up (Range: 24-36), 13.6% didn't achieve MCID for IPSS, and 7.2% for QoL scores. Significant hindrances to MCID attainment for IPSS were a large median lobe (> 10 mm protrusion) (OR = 3.01, 95% CI: 2.3-3.72), increased median lobe treatments (OR = 1.73, 95% CI: 1.23-2.35), and high preoperative irritative IPSS scores (OR = 1.25, 95% CI: 1.13-1.38). Factors for QoL MCID non-achievement included age over 75 (OR = 1.25, 95% CI: 1.13-1.38), a large median lobe (OR = 1.87, 95% CI: 1.62-2.01), and EPV over 60 cc (OR = 1.55, 95% CI: 1.16-1.97). A 6.3% surgical re-intervention rate was noted. Conclusions The characteristics of the median lobe as well as the severity of lower urinary tract symptoms are crucial for treatment success. These should be integral to preoperative assessments and patient discussions on treatment options.