Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy using PSMA-617 and PSMA-I&T ligands (Lu-PRLT) is an emerging treatment in metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of Lu-PRLT in earlier and later phases of mCRPC grouped by previous taxane chemotherapy. A retrospective analysis was performed on 167 patients with mCRPC who underwent Lu-PRLT between March 2013 and December 2016. Patients were classified as either taxane chemotherapy pretreated (T-pretreated) or naïve (T-naïve) depending on whether they had received taxane-based chemotherapy prior to Lu-PRLT. Clinical outcome for T-pretreated and T-naïve patients was assessed by overall survival (OS), radiographic progression-free survival, and prostate-specific antigen (PSA) response rate. Univariate and multivariable analyses were performed for both T-pretreated and T-naïve patients to determine predictors of outcome. Toxicity was categorized by the Common Terminology Criteria for Adverse Events (version 4.03). Of the 167 patients treated with Lu-PRLT, 83 were T-pretreated and 84 were T-naïve. At baseline, T-pretreated patients had overall poorer performance status, a higher prevalence of bone metastases, higher PSA levels, lower hemoglobin levels, higher alkaline phosphatase (ALP) levels and had received more additional therapies compared with T-naïve patients. Median OS was 10.7 mo for T-pretreated patients and 27.1 mo for T-naïve patients. Median radiographic progression-free survival was 6.0 mo for T-pretreated patients and 8.8 mo for T-naïve patients. PSA response assessment was evaluable in 132 patients and seen in 25 of 62 (40%) T-pretreated patients and 40 of 70 (57%) T-naïve patients. Significant determinates of inferior OS in multivariable analysis for T-pretreated patients were poorer performance status, lower cumulative administered activity, and lower baseline hemoglobin. Higher baseline alkaline phosphatase was the only significant determinate of inferior OS in multivariable analysis for T-naïve patients. Overall Lu-PRLT was safe, with minimal adverse effects evident during follow-up in both T-pretreated and T-naïve patients. Lu-PRLT is a promising therapy in mCRPC, with encouraging outcomes and minimal associated toxicity seen in both our T-naïve and heavily pretreated patient cohorts.