The objective is to estimate the extent to which existing health care interventions designed specifically to target health-related quality of life (HRQL) in persons with multiple sclerosis (MS) achieve this aim. The structured literature search was conducted using multiple electronic databases including Ovid MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Central Register of Controlled Trial, for the years 1960 to 2011. The methodological quality of selected randomized controlled trials (RCTs) was assessed using the Cochrane Collaboration's recommended domain-based method. Effect size (ES) was used to measure the effect of each intervention on HRQL. The studies were combined using a random-effects model to account for inter-study variation. Heterogeneity was tested for using the I-test and publication bias was assessed using funnel plots and the Egger weighted regression statistic. Thirty-nine RCTs met the criteria, all with acceptable methodological quality. Six major types of interventions were identified through the search. The smallest effect was observed for self-management and complementary and alternative medicine (ES=0.2), followed by medication (ES=0.3) then cognitive training and exercise (ES=0.4), and psychological interventions to improve mood (ES=0.7). The magnitude of positive effect on HRQL varied between the different types of interventions. The extent to which interventions are able to improve HRQL depends on delivering a potent intervention to those persons who have the potential to benefit.