Crohn's disease is a heterogeneous inflammatory disorder characterized by strictures or perforating complications. Information on natural history is limited. In the present study, 150 patients with long-standing Crohn's disease, including 81 females and 69 males, were seen continuously by a single clinician for at least 20 years. Additional retrospective data were available extending for >40 years and 13 have now died, usually with an advanced malignancy. To evaluate disease expression, phenotypic clinical characteristics defined by the 1998 Vienna classification for Crohn's disease were used and included age at diagnosis, location of disease, and disease behavior at the time of diagnosis or 10 years or 20 years after diagnosis. Most patients were initially diagnosed before the age of 40 years (94%) and had ileocolonic disease (65.3%). At diagnosis, both females and males were most often classified with inflammatory disease (nonstenosing, nonpenetrating); however, over the course of the disease, particularly in the first decade, decreased numbers of patients with inflammatory disease and increased numbers with penetrating disease were seen. In addition, some with stenosing disease eventually developed penetrating disease. Disease localized to ileum alone was most often complicated by stricture formation, whereas ileocolonic disease was usually complicated by a penetrating complication. This shift in disease behavior indicates that Crohn's disease is a dynamic process that phenotypically evolves and progresses with time.