Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, which involves an overreactive immune response causing damage to the host. There is a latitude-gradient effect that influences the prevalence of MS, whereby those closer to the equator are less likely to develop MS compared to those living further away. One large contributor to this effect is ultraviolet (UV) light from the sun, which has the capacity to suppress the immune response. It is hypothesised UV-induced immune suppression is responsible for this protective effect against MS. As such, we conducted a clinical trial (“PhoCIS”) to assess the effectiveness of phototherapy in delaying the onset of MS in patients with clinically isolated syndrome (CIS: a “pre-MS” disease). CIS patients were given phototherapy 3 time/week for 8 weeks. Peripheral blood-derived mononuclear cells were taken intermittently over the course of a year to investigate changes in circulating immune cells, and their correlation with disease outcome. As UV can activate regulatory B cells that are capable of suppressing the immune response, we used mass cytometry to phenotype and differentiate various B cell subsets. Our results revealed CIS and phototherapy affected various circulating B cell populations when compared to healthy controls. Although further functional assays are required to determine the exact role and function of these B cells, altered subsets may be potential targets in the treatment of CIS and MS.