Background: Targeted therapies (TT) have revolutionized treatment of mRCC with broad based efficacy and tolerability but ultimately all patients progress. While HD IL-2, the prior standard of care treatment, is associated with significant toxicities, it remains the only agent proven to elicit durable complete responses albeit rarely. This study evaluated trends in HD IL-2 use for patients with mRCC during the TT era. Methods: Our study cohort was comprised of a weighted sample of 2,351 patients with mRCC undergoing HDIL-2 treatment from 2004-2012, from the Premier Hospital Database (Premier Inc., Charlotte, NC), a nationally representative hospital discharge database. We employed descriptive statistics and fitted multivariable regression models, accounting for clustering and weighting, to identify predictors of treatment toxicity and tolerability. Results: We found a progressive decrease in the use of HD IL-2 from 2004 to 2008 with a general upward trend thereafter. HD IL-2 was increasingly concentrated at academic centers representing the site of treatment for 24% of patients in 2004 versus 90% of patients in 2012. Most patients were men (75.3%), Caucasian (70.7%) and aged <60 (59.6%) with lung metastases (60.9%) and otherwise healthy (64.72%, Charlson comorbidity index=0). Our adjusted analysis showed that severe hypotension was associated with patients <50 years (odds ratio [OR]: 1.35, p=0.045), while the likelihood of receiving ≥2 cycles of HDIL-2 was associated with good health (CCI=0, OR: 1.72, p=0.004) and having >1 metastatic site (OR: 4.32, p<0.001). Conclusions: Over the past decade, the use of HD IL-2 initially diminished coinciding with the widespread availability of TT but has remerged potentially due to renewed enthusiasm for immunotherapies showing promising efficacy with novel immune checkpoint inhibitors in mRCC. HD IL-2 has increasingly been limited to academic centers and our analysis suggests a strong selection bias for younger, healthier patients who can better tolerate the toxicities and those with a greater burden of metastatic disease. Future studies are warranted to determine the optimal role of HDIL-2 in the contemporary treatment of mRCC.