The adherence of clinical and commensal isolates and reference collection strains of Candida albicans to a human esophageal cell monolayer (HET1-A) and reconstituted human esophageal tissue was compared. Isolates from patients with a severe form of esophageal candidiasis or candidemia adhered to HET1-A cells to a significantly greater extent than did isolates from patients with mild esophageal candidiasis or commensal and reference collection strains. In addition, C. albicans strain SSK21, which lacks the ssk1 response regulator gene of a 2-component signal transduction pathway, adhered less readily to the HET1-A cells than did parental cells or a gene-reconstituted strain. In a reconstituted esophageal tissue model, all clinical strains but not commensal or reference collection strains penetrated the epithelium, albeit at different rates. Hyphal formation following yeast cell adherence to the esophageal tissue was a requirement for invasion. Scanning electron microscopy was also used to confirm the colonization of the esophageal tissues by various strains. These studies indicate that both the HET1-A and the reconstituted esophageal tissue models can be used as in vitro targets to evaluate the adherence phenotype and invasiveness of C. albicans strains.