Background The most compact portion of the corpus callosum (CC) is the corpus splenium (CS). Purpose To evaluate the connection between clinical and demographic features to determine whether neuroimaging findings will be permanent or temporary in CS patients. Material and Methods We enrolled 93 patients (age range = 18–86 years) with CS lesions. Demographic and clinical information were recorded. We examined the lesions depending on the location. Group 1 (n = 20) had lesions limited to the CS (egg-shaped or round); group 2 (n = 15) had “boomerang sign” lesions; and group 3 (n = 58) had splenium involvement in conditions affecting the whole brain (Boomerang sign+ plus). Results Group 1 had a lower mean age, shorter disease duration, and fewer persistent lesions than others ( P < 0.01, P < 0.001, and P < 0.001, respectively). The mean disease onset age (in years) in group 1 was higher than that of the other groups ( P < 0.045). Group 2 had lower potassium (K) ( P < 0.003) and red cell distribution width levels ( P < 0.029) than the other groups. Age <41.5 years ( P < 0.001), age at illness initiation <48.5 years ( P < 0.002), disease duration <5.5 months ( P < 0.001), and eosinophil level <0.29 uL ( P 0.014) all point to temporary lesions. Conclusion Cases with limited CS lesions have younger onset ages, lower disease onset ages, and shorter disease durations. Age, age of disease onset, disease duration, and eosinophil level are risk variables that affect whether CS lesions are permanent or temporary.