OBJECTIVE: Giant cell arteritis (GCA) is the most frequent form of vasculitis in adults. We sought to estimate the infectious risk associated with GCA and its treatment. METHODS: We conducted a matched historical cohort study using data from The Health Improvement Research Network. Patients with newly diagnosed GCA were matched with up to 6 non-GCA patients by age, sex, general practice, and date of entry into the cohort. Random-effects Poisson regression models were used to obtain incidence rates and rate ratios for lower respiratory tract infections (LRTI), urinary tract infections (UTI), and sepsis, as well as for the subset of these that comprised serious infections (pneumonias, upper UTI, and sepsis). Effect modification by age, sex, and time since diagnosis of GCA was assessed. RESULTS: A total of 1,664 patients with GCA were matched to 8,078 patients without GCA. Overall, 805 (48%) of the GCA patients and 3,007 (37%) of the non-GCA patients experienced ≥1 episode of systemic infection during followup, with adjusted rate ratios for LRTI, UTI, and serious infections of 1.48 (95% confidence interval [95% CI] 1.34-1.65), 1.27 (95% CI 1.10-1.46), and 1.55 (95% CI 1.22-1.96), respectively (P < 0.001 for all). The rate ratio for sepsis was 1.63 (95% CI 0.78-3.40, P = 0.20). Rate ratios for infection were highest in the first 6 months following diagnosis of GCA and in patients age <75 years, but did not vary by sex. CONCLUSION: This is the first study to show that patients with GCA are at increased risk of systemic infections, particularly in the first few months following diagnosis. New GCA medications that allow steroid sparing are needed to treat this condition.