Background: Studies in small groups of patients indicated that splenic volume (SV) may be decreased in patients with celiac disease (CD), refractory CD (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). Objective: The objective of this article is to evaluate SV in a large cohort of uncomplicated CD, RCD II and EATL patients and healthy controls. Methods: The retrospective cohort consisted of 77 uncomplicated CD (of whom 39 in remission), 29 RCD II, 24 EATL and 12 patients with both RCD II and EATL. The control group included 149 healthy living kidney donors. SV was determined on computed tomography. Results: The median SV in the uncomplicated CD group was significantly larger than in controls (202 cm3 (interquartile range (IQR): 154–275) versus 183 cm3 (IQR: 140–232), p = 0.02). After correction for body surface area, age and gender, the ratio of SV in uncomplicated CD versus controls was 1.28 (95% confidence interval: 1.20–1.36; p < 0.001). The median SV in RCD II patients (118 cm3 (IQR 83–181)) was smaller than the median SV in the control group (p < 0.001). Conclusion: This study demonstrates large inter-individual variation in SV. SV is enlarged in uncomplicated CD. The small SV in RCD II may be of clinical relevance considering the immune-compromised status of these patients.