The limbic system plays an important role in the emotion- and memory-related brain functions. In this study, we measured R2* and the volumes of the key elements of the limbic system and used them to detect abnormalities in the limbic system in multiple sclerosis (MS). The results showed significant differences between Secondary Progressive MS (SPMS) and healthy group. R2* of amygdala, thalamus, insula, lateral orbitofrontal and isthmus cingulate significantly correlate with clinical cognitive tests in female SPMS. Our results also showed that R2*-defined tissue alterations in the hippocampus and entorhinal cortex could identify depression behavior in MS patients.