SummaryVenous thromboembolism (VTE) is a well‐known complication in patients with acute lymphoblastic leukaemia (ALL) receiving asparaginase (ASP)‐based chemotherapy, including the ASP‐intensive Dana‐Farber Cancer Institute (DFCI) 91–01 protocol for adults. Since 2019, native L‐ASP is no longer available in Canada and was replaced by pegylated (PEG)‐ASP. To determine whether the incidence of VTE has changed since switching from L‐ASP to PEG‐ASP, we conducted a single‐centred retrospective cohort study. We included 245 adult patients with Philadelphia chromosome negative ALL between 2011 and 2021, with 175 from the L‐ASP group (2011–2019) and 70 from the PEG‐ASP group (2018–2021). During Induction, 10.29% (18/175) of patients who received L‐ASP developed VTE, whereas 28.57% (20/70) of patients who received PEG‐ASP developed VTE (p = 0.0035; odds ratio [OR] 3.35, 95% confidence interval [CI] 1.51–7.39), after adjusting for line type, gender, history of VTE, platelets at diagnosis. Similarly, during Intensification, 13.64% (18/132) of patients had VTE on L‐ASP while 34.37% (11/32) of patients on PEG‐ASP developed VTE (p = 0.0096; OR 3.96, 95% CI 1.57–9.96 with multivariable analysis). We found that PEG‐ASP is associated with a higher incidence of VTE compared to L‐ASP, both during Induction and Intensification, despite the administration of prophylactic anticoagulation. Further VTE mitigation strategies are needed in particular for adult patients with ALL receiving PEG‐ASP.