OBJECTIVES: In previous studies in chronic lymphocytic leukemia (CLL), adverse events (AEs) associated with commonly used therapies have primarily consisted of infusion reaction, myelotoxicity, and infection. This study estimated the cost of specific AEs per course of therapy associated with commonly used first-line treatment regimens for CLL in the United States. METHODS: This retrospective claims data analysis used Truven Health Analytics MarketScan® commercial and supplemental Medicare databases from January 2005 through August 2012. Eligible patients were ≥18 years, had a diagnosis of CLL, and continuous enrollment for ≥6 months prior to diagnosis. All patients received ≥1 dose of one of the following 5 regimens: fludarabine, cyclophosphamide, and rituximab (FCR); bendamustine plus rituximab (BR); chlorambucil, fludarabine plus rituximab (FR); or rituximab. AEs were identified from ICD-9-CM codes that either explicitly described the event of interest or that described interventions that were specific to the AE. Costs related to each AE were summed from diagnosis to the end of initial therapy. Drug costs of CLL therapies were excluded. Adjusted costs were estimated using a propensity-weighted generalized linear model (GLM), which controlled for differences in baseline characteristics across treatment groups. RESULTS: Of 2,035 patients, 497 received FCR, 130 received BR, 449 received chlorambucil, 297 received FR, and 662 received rituximab. Mean age was 69.5 years (SD: 12.4) and 64% were male. Comorbidities included diabetes (19%), COPD (16%), and cardiovascular (14%) disease. AE results (frequency; adjusted cost; and 95% CI, respectively) were as follows: infusion reaction (40%; $4482; $4141-$4862), anemia (35%; $8894; $8267-$9586), infection (26%; $7163; $6648-$7733), dyspnea (9%; $859; $751-$989), neutropenia (8%; $5406; $4629-$6367), febrile neutropenia (5%; $17,274; $14,374-$21,010), thrombocytopenia (2%; $12,621; $8933-$18,651), and leukopenia (1%; $1720; $1218-$2539). CONCLUSIONS: Infusion reaction, myelotoxicity, and infection have substantial economic costs in CLL, which may be reduced by improved patient management.