Dimethyl fumarate (DMF) and diroximel fumarate (DRF) are two treatments used in multiple sclerosis (MS), that have been shown to be effective in controlling MS patients. DRF was intro-duced in 2019, with the aim of decreasing the gastrointestinal side effects caused by DMF. Few real-life studies verify the data provided in the clinical trials. Methods: A retrospective descriptive study was conducted in MS patients at the Hospital Universitario Torrecárdenas under treatment with DRF and DMF. Demographic, clinical, and analytical variables were studied and compared between groups. Results: 60 patients were recruited, 30 with each treatment, observing similar baseline characteristics. Fewer gastrointestinal (GI) effects were observed in the DRF group, while more infections were detected in the DMF group. We recorded lower levels in the DRF group, with 4 moderate-severe lymphopenia in the DRF group vs. none in the DMF group. In addition, we observed a decrease in lymphocytes after the change from DMF to DRF in patients with a change. Conclusions: Our real-life analysis of patients treated with DMF or DRF supports studies’ findings of decreased GI side effects with DRF vs. DMF, without decreasing efficacy. However, our data show greater reduction in lymphocytes in patients with DRF compared to DMF, so more studies are necessary.