Background. Multiple sclerosis (MS) is one of the most common neurological disorders in the world. However, the cause(s) of MS is unknown. Studies have suggested that smoking may be related to the development and progression of MS. The Bradford Hill criteria are commonly used to assess potentially causal associations. However, to date, no systematic reviews and meta-analyses had used these criteria to comprehensively evaluate the relationship between smoking and MS. The objective of this research was to assess the relationship between smoking and both MS risk and MS progression through a systematic review and meta-analysis, subsequently applying Hill’s criteria to further assess the likelihood of these associations being causal. Methods. Databases including Medline, EMBASE, CINAHL, PsycInfo, and Cochrane Library were searched for relevant studies up until July 28, 2015. A random-effects meta-analysis was conducted for three outcomes: MS risk, conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS), and progression from relapsing-remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS). Consideration was given to dose-response relationships and risk factor interactions, and discussions of mechanisms and analogous associations presented in the studies. Hill’s criteria were applied to assess causality of the relationships between smoking and each outcome. The effect of second-hand smoke exposure was also briefly reviewed. Results. Smoking had a statistically significant association with both MS risk (conservative: OR/RR 1.54, 95% CI [1.46-1.63]) and SPMS risk (HR 1.80, 95% CI [1.04-3.10]), but the association with progression from CIS to CDMS was non-significant (HR 1.13, 95% CI [0.73-1.76]). Based on Hill’s criteria, there was strong evidence of a causal role of smoking in MS risk, but only moderate evidence of a causal association between smoking and MS progression. Heterogeneity in study designs and target populations, inconsistent results, and an overall scarcity of studies point to the need for more research in the area of second-hand smoke exposure in relation to MS prior to conducting a detailed metaanalysis. Conclusion. This first review to supplement systematic review and metaanalytic methods with the application of Hill’s criteria to analyze the smoking-MS association provided evidence supporting the causal involvement of smoking in the development and progression of MS. As such, smoking cessation programs and policies should highlight MS as an additional health risk to deter the public from smoking. Keywords: Multiple sclerosis; cigarette smoking; clinically isolated syndrome; Bradford Hill