Background: Patients with del17p or TP53^mut AML have a dismal prognosis marked by high relapse rates and short survival. The addition of venetoclax to a hypomethylating agent (HMA; decitabine or azacitidine) improved overall survival in AML compared to HMA monotherapy for non-induction candidates. However, data on the relative efficacy of venetoclax combination therapy in adverse-risk molecular groups remains sparse outside of clinical trials. The purpose of this study was to determine the efficacy of venetoclax combination therapy in patients with del17p or TP53^mut AML, using HMA monotherapy as a comparison. Methods: We retrospectively analyzed 35 patients with del17p or TP53^mut AML treated with venetoclax + HMA or HMA alone from January 1, 2013 to January 1, 2022 at VCU Massey Cancer Center. Patients were treated in the front-line setting and separated into two cohorts: those treated with venetoclax + HMA or HMA monotherapy. To reduce confounding effects, patients that received venetoclax following initiation of HMA monotherapy were excluded from the monotherapy arm. We recorded baseline patient and disease characteristics, cytogenetic risk, response, and survival. We used Fisher’s exact test for nominal data and Mann-Whitney for ordinal data. We analyzed survival by the Kaplan-Meier method and compared groups with the log-rank test. Results: We identified 35 patients with del17p or TP53^mut AML treated with venetoclax + HMA or HMA monotherapy in the first line. Twenty-one (60.0%) patients were in the venetoclax combination arm, and 14 (40.0%) were in the monotherapy arm. There were no significant between-group differences in age (72 vs 74, p = 0.303), ECOG score (2 vs 1, p = 0.292), or Charlson Comorbidity Index score (6 vs 7, p = 0.211) between the combination and monotherapy arms, respectively. The median TP53^mut variant allele frequency (VAF) was 35.5% in the venetoclax cohort and 42.2% in the HMA cohort (p = 0.479). The composite complete remission (CCR) rate significantly favored the venetoclax arm at 40.0% (95% CI, 21.9 - 61.3), compared to 0% (95% CI, 0 - 27.8) in the monotherapy arm (p = 0.029). Furthermore, the median overall survival significantly favored the venetoclax cohort at 6.0 months compared to 3.4 months in the HMA cohort (p = 0.026). Strikingly, in the venetoclax combination arm, we identified that a TP53^mut VAF threshold of less than 35.0% predicted superior survival at 11.8 months compared to 2.8 months for VAF of greater than 35% (p = 0.035). The identification of a similar VAF threshold was limited in the monotherapy arm due to the availability of NGS data. Conclusions: The addition of venetoclax offers significantly superior response and survival compared to HMA monotherapy in patients with del17p or TP53^mut AML. We identified a novel TP53^mut VAF threshold of 35.0% that predicts superior survival with combination therapy. The clinical use of this threshold requires prospective validation.