OBJECTIVES: Assess economic costs of adverse events (AEs) among patients with human immunodeficiency virus (HIV) treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) including delavirdine, efavirenz, etravirine, and nevirapine. METHODS: Retrospective cohort study using medical and pharmacy claims from US commercial or Medicare supplemental insurance patients between January 1, 2004 to September 30, 2009. Adult HIV-patients initiating NNRTI (no NNRTI use during 6 months prior to first dispensation [index date]) were selected. AEs included rash, nausea/vomiting, diarrhea, dizziness, headache, sleep-related symptoms, hepatotoxicity, lipid disorders, depression, anxiety, and self-injury. AE episode-related care during the year post-initiation was identified by claims associated with AE management. AE cases were matched 1:4 to non-AE controls by propensity of having an AE. “Associated costs” included plan payments and patient copayments directly related to managing AEs. “Incremental costs” of experiencing an AE were calculated as the difference in total costs between patients with AE during the period of each AE episode and non-AE controls (matched period). RESULTS: The study included 2548 NNRTI users (mean age 43 years; 84% male; 87% efavirenz; 29% experienced an AE). During 1-year post-index period, annual total healthcare cost per patient in this study population was $27,751 (efavirenz: $26,704; other NNRTIs: $34,993). Annual mean AE associated costs were $609 per patient (efavirenz: $555; other NNRTIs: $979). Mean AE associated cost of care (duration) per AE episode ranged from $586 (88 days) for lipid disorders, $975 (33 days) for rash, to $2,728 (78 days) for sleep-related symptoms and $4,434 (41 days) for nausea/vomiting. Mean incremental cost per AE episode ranged from $1,581 (rash), $2,033 (lipid disorders) to $12,834 (nausea/vomiting) and $22,321 (sleep-related). CONCLUSIONS: Treatment-associated AEs are now essential considerations with increased HIV patient longevity. In addition to clinical implications, economic costs should be considered in NNRTI-containing treatment regimen decisions and for estimating cost-effectiveness of therapy.