Idiopathic inflammatory bowel disease (IBD) and gastrointestinal lymphoma are common disorders in cats. The aim of this study was to evaluate fecal α(1)-PI concentrations, a marker of gastrointestinal protein loss, in cats with histopathological evidence of gastrointestinal inflammation or gastrointestinal neoplasia. Fecal and serum samples were obtained from 20 cats with chronic gastrointestinal disease in which endoscopic biopsies were performed. Two groups of cats were assembled based on histopathology: Group A (n = 8), mild to moderate IBD; Group B (n = 12), severe IBD or gastrointestinal neoplasia. Fecal α(1)-PI concentrations and serum concentrations of total protein, albumin, globulin, cobalamin, folate, pancreatic lipase immunoreactivity, and trypsin-like immunoreactivity were determined. Nineteen of the 20 diseased cats had elevated fecal α(1)-PI concentrations, ranging from 1.9 to 233.6 μg/g compared to 20 healthy control cats (normal range: ≤1.6 μg/g). Fecal α(1)-PI concentrations were statistically significantly different between healthy cats and cats of Group A (median: 3.9 μg/g, range: 1.3-9.2 μg/g, P < 0.001) or cats of Group B (median: 20.6 μg/g, 4.3-233.6 μg/g; P < 0.001), and between cats of Groups A and B (P < 0.01). Hypoalbuminemia, hypoproteinemia, and hypocobalaminemia were detected in 88%, 83%, and 56% of the diseased cats, respectively. This study suggests that increased fecal α(1)-PI concentrations in association with low serum albumin and total protein concentrations may be a common finding in cats with IBD or gastrointestinal neoplasia. Furthermore, fecal α(1)-PI concentrations appear to be higher in cats with severe IBD or confirmed gastrointestinal neoplasia when compared to cats with mild to moderate IBD.