A total of 548 patients (age range: 1-22 years, 60.4% Hispanic, 55.8% male) diagnosed with acute lymphoblastic leukemia were reviewed for pegaspargase-associated hypersensitivity (14.8%), hyperbilirubinemia (9.7%), venous thromboembolism (VTE, 9.7%), and pancreatitis (5.3%). Odds ratios (OR) and 95% confidence intervals (CI) evaluated associations between clinical factors and each toxicity, cumulative number of toxicities, and toxicity clusters identified using k-mode analysis. Most (68.9%) did not experience any toxicity, 24.6% experienced one toxicity, and 6.3% two or more. Age10 years was associated with hyperbilirubinemia (OR = 3.83; 95% CI: 1.64-8.95), pancreatitis (OR = 3.72; 95% CI: 1.29-10.68), VTE (OR = 4.65; 95% CI: 1.96-11.02), and cumulative toxicity burden (OR = 3.28, 95% CI: 1.97-5.47); high-risk therapy with hypersensitivity (OR 2.25; 95% CI 1.25-4.05); and overweight with cumulative toxicity burden (OR = 1.76, 95% CI: 1.20-2.57). Eight unique toxicity profiles were identified. Older age, overweight, and treatment intensity contribute to pegaspargase-associated toxicities.