Therapy‐related acute promyelocytic leukemia (t‐APL) is a well‐recognized form of APL for which the underlying etiology has been well characterized. The pathogenesis of de novo (dn‐APL) remains unknown; but epidemiologic studies have consistently identified increased body mass index (BMI), younger age, and ethnicity as possible risk factors. We analyzed demographics, clinical features, and treatment responses in a contemporary series of 64 patients treated with all‐trans‐retinoic acid and anthracycline‐based therapy to assess for differences in these two etiologically distinct patient groups. Compared with patients with t‐APL (n = 11), those with dn‐APL (n = 53) had a greater median BMI (31.33 vs. 28.48), incidence of obesity (60.4% vs. 27.3%) (P = 0.04), and history of hyperlipidemia (45.3% vs. 18.2%) (P = 0.01). Fewer t‐APL than dn‐APL patients achieved complete remission at 63.6% vs. 92.5% respectively (P = 0.008). This was the result of a higher induction mortality rate of 36.4% vs. 7.5% respectively (P = 0.008). No cases of leukemic resistance were seen in either group. Overall survival (OS) was inferior in t‐APL compared with dn‐APL at 51% vs. 84%, respectively (P < 0.005), primarily as a result of higher induction mortality. Relapse occurred in nine patients (16.1%) overall, but no relapses occurred in the t‐APL cohort. Our observations provide further support for the hypothesis that abnormalities in lipid homeostasis may in some way be of pathogenic importance in dn‐APL. Therapy‐related APL is sensitive to standard therapy with no cases of resistance or relapse seen. The inferior OS of the t‐APL was due to induction mortality, possibly reflecting prior therapy.