Enzyme replacement therapy (ERT) for Pompe disease using recombinant acid alpha‐glucosidase (rhGAA) has resulted in increased survival although the clinical response is variable. Cross‐reactive immunological material (CRIM)‐negative status has been recognized as a poor prognostic factor. CRIM‐negative patients make no GAA protein and develop sustained high antibody titers to ERT that render the treatment ineffective. Antibody titers are generally low for the majority of CRIM‐positive patients and there is typically a better clinical outcome. Because immunomodulation has been found to be most effective in CRIM‐negative patients prior to, or shortly after, initiation of ERT, knowledge of CRIM status is important before ERT is begun. We have analyzed 243 patients with infantile Pompe disease using a Western blot method for determining CRIM status and using cultured skin fibroblasts. Sixty‐one out of 243 (25.1%) patients tested from various ethnic backgrounds were found to be CRIM‐negative. We then correlated the CRIM results with GAA gene mutations where available (52 CRIM‐negative and 88 CRIM‐positive patients). We found that, in most cases, CRIM status can be predicted from GAA mutations, potentially circumventing the need for invasive skin biopsy and time wasted in culturing cells in the future. Continued studies in this area will help to increase the power of GAA gene mutations in predicting CRIM status as well as possibly identifying CRIM‐positive patients who are at risk for developing high antibody titers. © 2012 Wiley Periodicals, Inc.