BACKGROUND: Chronic granulomatous disease (CGD) is an uncommon primary immunodeficiency that can be inherited in an X-linked (XL) or an autosomal recessive (AR) manner. We reviewed our large, single-center US experience with CGD. METHODS: We reviewed 27 patients at Ann & Robert H. Lurie Children's Hospital of Chicago from March 1985 to November 2013. Fisher exact test was used to compare differences in categorical variables, and Student t test was used to compare means for continuous variables. Serious infections were defined as those requiring intravenous antibiotics or hospitalization. RESULTS: There were 23 males and 4 females; 19 were XL and 8 were AR. The average age at diagnosis was 3.0 years; 2.1 years for XL and 5.3 years for AR inheritance (P = 0.02). There were 128 serious infections. The most frequent infectious agents were Staphylococcus aureus (n = 13), Serratia (n = 11), Klebsiella (n = 7), Aspergillus (n = 6) and Burkholderia (n = 4). The most common serious infections were pneumonia (n = 38), abscess (n = 32) and lymphadenitis (n = 29). Thirteen patients had granulomatous complications. Five patients were below the 5th percentile for height and 4 were below the 5th percentile for weight. Average length of follow-up after diagnosis was 10.1 years. Twenty-four patients were compliant and maintained on interferon-gamma, trimethoprim-sulfamethoxazole and an azole. The serious infection rate was 0.62 per patient-year. Twenty-three patients are alive (1 was lost to follow-up). CONCLUSIONS: We present a large, single-center US experience with CGD. Twenty-three of 27 patients are alive after 3276 patient-months of follow-up (1 has been lost to follow-up), and our serious infection rate was 0.62 per patient-year.