Objective: Fingolimod is approved for the treatment of highly active relapsing remitting multiple sclerosis (MS) patients and acts by its unique mechanism of action via sphingosine-1-phosphate receptor-modulation. Although fingolimod-associated lymphopenia is a well-known phenomenon, the exact cause for the intra- and inter-individual differences of the fluctuation of lymphocyte count and its subtypes is still subject of debate. In this analysis, we aim to estimate the significance of the individual variation of distinct lymphocyte subsets for differences in absolute lymphocyte decrease in fingolimod treated patients and discuss how different lymphocyte subset patterns are related to clinical presentation in a long-term real life setting. Methods/Design: One hundred and thirteen patients with MS were characterized by complete blood cell count and immune cell phentopying of peripheral lymphocyte subsets before, at month 1 and every 3 months up to 36 months of fingolimod treatment. In addition, patients were monitored regarding clinical parameters (relapses, disability, MRI). Results: There was no significant association of baseline lymphocyte count and lymphocyte subtypes with lymphocyte decrease after fingolimod start. The initial drop of the absolute lymphocyte count could not predict the level of lymphocyte count during steady state on fingolimod. Variable CD8+ T cell and NK cell counts account for the remarkable intra- and inter-individual differences regarding initial drop and steady state level of lymphocyte count during fingolimod treatment, whereas CD4+ T cells and B cells mostly present a quite uniform decrease in all treated patients. Selected patients with lymphocyte count >1.0 GPT/l differed by higher CD8+ T cells and NK cell counts compared to lymphopenic patients but presented comparable clinical effectiveness during treatment. Conclusion: Monitoring of the absolute lymphocyte count at steady state seems to be a rough estimate of fingolimod induced lymphocyte redistribution. Our results suggest, that evaluation of distinct lymphocyte subsets as CD4+ T cells allow a more detailed evaluation to weigh and interpret degree of lymphopenia and treatment response in fingolimod treated patients.