Objective The aim of this study was to evaluate the reproducibility of measurement of spleen stiffness at the time of the initial detection of splenomegaly, whether it is found incidentally or not, in determining the etiology of splenomegaly. Methods The pathologies that brought about the diffuse splenomegaly were evaluated in 3 main groups as follows: hepatoportal, myeloproliferative, and infectious causes. In addition, 17 healthy control patients were recruited. All patients were examined with acoustic radiation force impulse imaging with VTQ. Results The difference between the splenic parenchymal elasticity values in the hepatoportal group (3.27 +/- 0.36 m/s), in the myeloproliferative disease group (2.98 +/- 0.33 m/s), in the infectious disease group (2.44 +/- 0.21 m/s), and in the control group (2.08 +/- 0.19 m/s) was found to be statistically significant (P = 0.001). The intraclass correlation coefficient for shear wave velocity measurement between hepatoportal causes and myeloproliferative causes was 71.2% (95% confidence interval [CI], 54.9%-87.4%), between hepatoportal causes and infective causes was 99.7% (95% CI, 98.6%-100.0%), and between myeloproliferative causes and infective causes was 83.3% (95% CI, 68.8%-97.9%). In the same patient groups, spleen volumes were measured as 64.08 +/- 9.66, 78.18 +/- 18.52, and 51.57 +/- 7.44 cm(2), respectively; in the control group, it was 26.75 +/- 6.57 cm(2). The difference between spleen volumes was found to be statistically significant (P = 0.001). Conclusions Distinguishing the causes of splenomegaly is important because the disorders require different management strategies. In diseases that cause splenomegaly, tissue content may change according to pathogenesis. Such changes in the spleen are mechanical properties that can be quantified by elastography.