Background: Sleep disturbance in persons with multiple sclerosis (pwMS) is associated with fatigue, depression, future cognitive decline, and worse quality of life (QOL). Fatigue in pwMS is independently associated with reduced QOL regardless of sleep quality. PwMS have often prescribed both hypnotics and stimulants concomitantly. Still, no large studies have investigated the influence of dual symptomatic therapy on daytime fatigue, sleep disturbance, and QOL in pwMS. Objectives: Our objective was to evaluate the effects of concomitant use of hypnotics and stimulants on QOL measures in pwMS. We hypothesized that pwMS with concurrent use of both stimulants for the treatment of fatigue and hypnotics for the treatment of sleep disturbance might report lower QOL as compared to those taking either none or only one of these medication classes individually. Methods: We conducted a cross-sectional study in patients enrolled in the ongoing 10-site MS Partners Advancing Technology and Health Solutions (MS PATHS) database. PwMS completed the Quality of Life in Neurological Disorders (Neuro-QoL) instrument as part of one of their routine clinical visits. Current medications were abstracted from the electronic medical record. Participants were divided into groups according to their exposure to different symptomatic therapies. Multivariable-adjusted (demographic characteristics, BMI, MS characteristics, comorbidities, disability, and smoking status) generalized linear models were used to assess for differences in QoL between groups. Results: Within our cohort of 10,859 participants (age 50.8 + 12.2 years, MS duration 14.3 + 12.6 years, 74.3% women, 8.97% Black, 22.4% progressive MS), 414 were on both hypnotic and stimulant medications, 2,784 were on stimulants only, 474 were on hypnotics only, and 7,187 were not on any of these therapies. When compared to pwMS receiving neither stimulants nor hypnotics, those receiving dual therapy had higher odds of self-reporting moderate-to-severe sleep disturbance (OR 3.4; CI=2.4-4.8), fatigue (OR 4.0; CI=2.8-5.7), anxiety (OR 2.3; CI=1.6-3.4), depression (OR 2.5; CI=1.7-3.6), and cognitive disturbance (OR 3.4; CI=2.4-4.8). Conclusions: PwMS with concurrent use of hypnotics and stimulants had worse self-reported QOL as compared to those receiving either none or one of those medication classes individually. Longitudinal studies on the effect of MS symptomatic therapies on QOL and symptom management effectiveness and that address the possibility of confounding by indication are warranted to determine their role in the treatment of pwMS.