Lacunar infarction has long been considered to be associated with good prognosis, however a significant percentage of these patients remain functionally dependent. In this study we sought to investigate the factors associated with poor outcome in patients with lacunar infarction. <i>Subjects and Methods:</i> We have performed a secondary study in 113 patients with lacunar infarctions admitted within the first 24 h of symptom onset (mean age 70 years, 57.5% men). Blood pressure, body temperature, serum glucose levels, neurotransmitters and pro-inflammatory markers were measured at admission and during the first 72 h. Stroke severity was assessed by the Canadian Stroke Scale (CSS). Neuroimaging evaluation was performed at admission and between days 4 and 7. Poor functional outcome was considered as a Barthel index <85 at 3 months. <i>Results:</i> 36 patients (31.9%) had poor outcome. Older age (p = 0.009), history of hypertension (p = 0.005), higher body temperature (p < 0.0001), systolic blood pressure (SBP) (p = 0.010), serum glucose (p = 0.002) and interleukin-6 (IL-6) (p < 0.0001) levels, as well as lower CSS score at admission (p < 0.0001) were all predictive factors of poor outcome in bivariate analyses. SBP at admission (OR 2.07, CI 95% 1.04–3.28, p = 0.015) was the only clinical predictor on multivariate analysis. When the logistic model was further adjusted for biomarkers of inflammation and excitotoxicity, IL-6 levels (OR 1.09, CI 95% 1.01–1.26, p = 0.003), but not SBP, was independently associated with poor outcome. This association persisted even after adjusting for potential predictors recorded during the first 72 h of hospitalization. <i>Conclusion:</i> High SBP and IL-6 levels on admission may predict poor outcome in patients with lacunar infarction.