Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive and rare hematologic malignancy characterized by poor response to multiagent chemotherapy and dismal survival outcomes of 8-16 months. Tagraxofusp, the first-in-class CD123-directed antineoplastic agent, has emerged as a highly effective therapy and is the only FDA approved drug for BPDCN. Nonetheless, significant treatment-related toxicities with tagraxofusp such as hepatotoxicity and capillary leak syndrome are unfortunately not uncommon and can be prohibitive for older or unfit patients. The success of venetoclax (VEN) with a hypomethylating agent (HMA) has recently been described in the literature however, clinical outcomes are limited to case reports and small case series. To confirm these findings, we performed a multicenter, retrospective cohort study utilizing the TriNetX Networks database to compare survival outcomes between BPDCN patients (≥60 years-of-age) who received VEN + HMA versus tagraxofusp. In total, 32 and 39 patients received VEN + HMA and tagraxofusp, respectively, between February 1, 2019 and September 1, 2024. Median follow-up time was 7.4 and 9.3 months in the VEN + HMA and tagraxofusp cohorts, respectively. Overall survival (OS) between VEN + HMA and tagraxofusp-treated patients was comparable at 12-months (41.2% vs. 53%; HR 1.15; 95% CI, 0.53-2.48; P = 0.73). In a subgroup analysis of older adult patients (≥75 years-of-age), OS at 12-months (38.1% vs. 56.5%; HR 1.20; 95% CI, 0.47-3.04; P = 0.71) was not significantly different. In conclusion, this large-scale, retrospective database analysis suggests that VEN + HMA is an effective therapeutic alternative to tagraxofusp in older patients for the management of BPDCN. Future studies are needed to prospectively validate these findings.