Background: Prior work investigating the optimal dose of daunorubicin in combination with cytarabine for upfront treatment of AML has resulted in several studies suggesting differential responses following daunorubicin dose optimization when analyzed by molecular cohort (such as NPM1, FLT3-ITD, or DNMT3A). While some studies advocated for a dose of 90 mg/m² in younger patients with NPM1^mut (following induction with either daunorubicin 45 mg/m² versus 90 mg/m²), little is known regarding outcomes stratified by molecular lesion between daunorubicin 60 mg/m² and daunorubicin 90 mg/m². Methods: We retrospectively analyzed 92 patients with AML treated with upfront daunorubicin 60 mg/m² or 90 mg/m² from July 2017 to December 2020 at VCU Massey Cancer Center. Baseline patient demographics were obtained, including cytogenetic risk, molecular profiling either through PCR or NGS at the time of induction, doses of induction regimens, response including MRD analysis (when available), and survival. Results: In the 60 mg/m² cohort, 10 patients had NPM1^mut, theCRR (CR+CRi) was 60.0% and the OS was 1.7 y. Four patients with DNMT3^mut had a CRR of 25.0% and a 4.1 m. OS. Nine patients with FLT3-ITD or FLT3-TKD all treated with FLT3 inhibitors achieved a CRR of 22.2% with a 4.9 m. OS. Ten patients with NRAS^mut or KRAS^mut had a CRR of 50.0% and a 20.7 m. OS. In the adverse category, five with ASXL1^mut had a 20.0% CRR and a 6.4 m. OS; 7 with RUNX1^mut had a CRR of 42.9% and a 14.5 m. OS; and 6 with TP53^mut demonstrated a CRR of 0% and an 13.1 m. OS. In the 90 mg/m² cohort, 8 patients had NPM1^mut with a CRR of 75.0% and an 18.8 m. OS. Two patients with DNMT3^mut both achieved CR and the OS was not reached. Three of 5 patients with FLT3^mut treated with midostaurin achieved CR or CRi and a 16.2 m. OS. Four of 5 patients with RAS^mut achieved CR and the OS was not reached at a 15.8 m. follow-up time. In the adverse category, there were no patients treated with a dose of 90 mg/m² with ASXL1^mut and one with RUNX1^mut with non-evaluable response. Two out of 4 patients achieved CR or CRi with TP53^mut and the OS was not reached. Conclusions: Response rates appear numerically higher across molecular subtypes favoring daunorubicin 90 mg/m², although no significant differences in survival were appreciated, likely due to limited sample size. This may argue for intensification of anthracycline doses in carefully selected patients regardless of molecular profiling. Toxicity with high-dose daunorubicin must be weighed against any potential response or survival benefit, particularly for TP53^mut and ASXL1^mut – especially in the setting of alternative induction strategies such as CPX-351 and venetoclax with a hypomethylating agent. Larger prospective studies analyzing outcomes with regards to molecular profiling and treatment strategies are warranted.