Background: Abacavir hypersensitivity reaction (ABC HSR) is a potentially fatal syndrome occurring in 5% (range 0-14%) of patients treated with ABC. Nine (18%) of 50 individuals treated with ABC at the Seattle Primary Infection Clinic developed ABC HSR. This study examined possible explanations for this increased rate of ABC HSR. Methods: Through Acute HIV Infection and Early Disease Research Program (AIEDRP) protocol AI-02-001, subjects presenting during primary infection were offered antiretroviral therapy including ABC. Cases of ABC HSR were identified prospectively by study clinicians and confirmed retrospectively. Controls were the cohort receiving ABC without hypersensitivity. Univariate analyses were performed by logistic regression. Results: Subjects were male with mean age of 33.3 years. Two (22.2%) of 9 cases had the HLA-B*5701 polymorphism compared to 0 of 39 tested controls (p=.032 by Fisher's exact test). At baseline cases had lower percentage of CD8⁺ T-cells (p=.012) and lower levels of HIV RNA (p=.037). Approximately 2 weeks into therapy, cases continued to have lower levels of HIV RNA (OR .212 per log, p=.024) with a trend for cases to have had a greater decrease in RNA (OR 4.63 per log, p=.088). In addition, there was a trend towards association of ABC HSR with initiation of ABC later within primary infection; cases began therapy a median of 103 days after HIV acquisition compared to 48 days in controls (OR 1.02 per day, p=.086). Conclusions: 1) Due to the high rate of ABC HSR, abacavir should be used with caution or avoided in regimens initiated during primary HIV infection. 2) As in chronic HIV infection, HLA-B*5701 is associated with ABC HSR in primary infection. 3) Although levels of CD8⁺ T-cells and HIV RNA may be independent risk factors for ABC HSR, the observed association may be due to correlation with HLA-B*5701. 4) The temporal association of ABC HSR with initiation of ABC in later primary infection indicates a focus for future research.