Background and Purpose-A prespecified interaction analysis of the neutral Intravenous Magnesium Efficacy in Stroke ( IMAGES) trial revealed significant benefit from magnesium (Mg) in patients with noncortical stroke. Post hoc analysis indicated that this effect was seen in lacunar clinical syndromes (LACS), interaction P = 0.005. We have now examined whether this interaction could be explained by confounding baseline factors. Methods-LACS was defined on the basis of neurological signs and did not include imaging. We investigated the interaction between baseline variables and Mg treatment on global outcome. We used logistic-regression models to test whether the Mg-LACS interaction remained significant after adjusting for stratification variables, sex, a novel stroke severity score, and baseline variables that had an interaction with treatment (P < 0.1). Results-The Mg (n = 383) and placebo (n = 382) groups of LACS patients were well matched on baseline factors. In addition to LACS, we found an interaction between beneficial Mg treatment effect and younger age (P = 0.003), higher baseline diastolic blood pressure (P = 0.02), higher mean blood pressure (P = 0.02), and absence of ischemic heart disease (P = 0.07). Even so, the adjusted Mg-LACS interaction remained significant (odds ratio [OR] 0.57; 95% CI, 0.39 to 0.83; P = 0.003). In the LACS subgroup, Mg improved Barthel Index < 95 (OR 0.73; 95% CI, 0.55 to 0.98), modified Rankin Scale > 1 (OR 0.67; 95% CI, 0.50 to 0.91), and global outcome (OR 0.70; 95% CI, 0.53 to 0.92) but not Barthel Index < 60 or mortality. Conclusions-The positive treatment effect of Mg in LACS cannot be ascribed to general issues of severity, time to treatment, blood pressure, or other baseline factors; equally, this finding may be due to chance. A large trial of Mg treatment in LACS appears justified.