A number of entities can simulate pancreatic disease at computed tomography (CT), which may lead to misdiagnosis. Common pitfalls include peripancreatic lesions of the foregut, adrenal gland, and kidney as well as disease of the mesentery and neurovascular structures. Optimal design and application of multi-detector row CT protocols with multiplanar reformation and maximum-intensity-projection and volume-rendering postprocessing improves the specificity of image interpretation. In most cases, helical CT is highly accurate for distinguishing primary disease of the pancreas from adjacent disease, although there are cases in which the differential diagnosis is more challenging and the potential for misdiagnosis still exists. Familiarity with some of the entities that can simulate pancreatic disease, careful attention to scanning protocol and contrast material administration, use of the full potential of multi-detector row CT data sets, and judicious application of postprocessing tools may help avoid some of the pitfalls caused by peripancreatic lesions.