Purpose We investigated the role of PSMA-derived tumor burden in predicting docetaxel (DTX) therapy response in metastatic castration-resistant prostate cancer (mCRPC). Methods Fifty-two mCRPC patients who received at least six cycles of DTX as the first-line treatment following Ga-68-PSMA PET/CT were enrolled in this retrospective study. Total PSMA-derived tumor volume (TV-PSMA) and total lesion PSMA activity (TL-PSMA) were derived from metastatic lesions. A >= 50% decline in PSA was defined as a response; a >= 25% increase in PSA was defined as progression. Univariate/multivariate logistic and cox regression analyses were performed to predict PSA response, OS, and TTP. Results Twelve (23%) patients had PSA progression after chemotherapy, while 40 patients (77%) achieved a PSA response. On univariate analysis, a significant association was found between TV-PSMA (p = 0.001), TL-PSMA (p = 0.001), pre-PSA (p = 0.012), LDH (p = 0.003), Hg (p = 0.035), and PSA response to DTX. High TV-PSMA (> 107 cm(3)) (p = 0.04) and high LDH (> 234 U/L) (p = 0.017) were 8.2 times and 12.2 times more likely for DTX failure in multivariate regression analyses. The median TTP was 16 months, and the median OS was not reached. Patients with high TV-PSMA (p = 0.017), high TL-PSMA (> 1013 cm(3)) (p = 0.042), high age (> 70 years) (p = 0.016), and high LDH (p <= 0.001) had significantly shorter OS, while only high TV-PSMA (p = 0.038) and high age (p = 0.006) were significantly related with shorter TTP. High TV-PSMA (p = 0.017) and high age (p = 0.01) were significant predictors for shorter OS, while only high age (p = 0.006) was a significant predictor for shorter TTP in multivariate analysis. Conclusion Patients with high TV-PSMA had a significantly higher risk for DTX failure. PSMA-based tumor burden prior to DTX therapy seems to be a reliable predictive tool for survival in mCRPC patients.