Background: Space-occupying middle cerebral artery brain infarcts are associated with the development of brain edema, which may lead to cerebral herniation and death despite early hemicraniectomy. Aims: To evaluate the benefit of therapeutic hypothermia in patients with space-occupying cerebral infarction treated with hemicraniectomy within 48 h of stroke onset. Methods: Patients aged 18–60 years with space-occupying cerebral infarction treated with hemicraniectomy within 48 h and hypothermia (33–34°C) were selected from a single university hospital between 2001 and 2010 (n = 53). Patients treated with hemicraniectomy alone served as comparison group (n = 58), originating from three randomized controlled trials evaluating the effects of early decompressive surgery (DECIMAL, DESTINY, HAMLET). Primary outcome was the score on the modified Rankin scale at 12 months dichotomized between modified Rankin scale 0–3 and modified Rankin scale 4–6. Secondary outcome measures were modified Rankin scale score 0–4 and survival. Risk ratios were adjusted with Poisson regression. Results: Mean patient age was 48 years. Median time from stroke onset to hemicraniectomy was 23.5 h in both treatment groups. Treatment with hypothermia had no effect on the primary outcome (modified Rankin scale 0–3 versus 4–6 (13/53 (25%) versus 24/58 (41%)); adjusted risk ratio 0.66, 95% confidence interval 0.38–1.13). Fewer patients treated with hypothermia had a modified Rankin scale score of 0–4 (21/53 (40%) versus 42/58 (72%); adjusted risk ratio 0.53, 95% confidence interval 0.37–0.76) and fewer patients survived (26/53 (49%) versus 46/58 (79%); adjusted risk ratio 0.60, 95% confidence interval 0.44–0.82). Conclusions: In patients with space-occupying cerebral infarction, treatment with hypothermia had no additional benefit on functional outcome compared with treatment with hemicraniectomy alone.