Abstract Objectives To evaluate if the hyperdense middle cerebral artery sign (HMCAS) is an imaging biomarker for hemorrhagic transformation (HT) and the functional outcome of patients with large cerebral infarctions without thrombolytic therapy. Materials and Methods The clinical and imaging data of 312 patients with large cerebral infarction without thrombolytic therapy were retrospectively analyzed. They were divided into patients who presented with HMCAS ( n = 121) and those who did not (non‐HMCAS[ n = 168] patients), and the clinical data of the 2 groups were compared. This was a retrospective study. Results Of the 289 patients, 83(28.7%) developed HT. The incidence of atrial fibrillation, high homocysteine and admission NIHSS score at the time of admission was significantly higher in the HMCAS patients than in non‐HMCAS patients ( p < .05). The ASPECTS was significantly lower in HMCAS patients ( t = −5.835, p  < .001). The incidence of PH‐2 and 3‐month mRS score was also statistically significant higher in HMCAS patients (χ 2 = 3.971, p = .046; χ 2 = 5.653, p  < .001, respectively). A sub‐analysis showed HMCAS patients with HT were significantly older than non‐HMCAS patients with HT ( t  = 2.473, p = .015). The incidence of atrial fibrillation and the 3‐month mortality rate were higher in HMCAS patients with HT than in non‐HMCAS patients with HT (χ 2 = 3.944, p = .047; χ 2 = 6.043, p = .014, respectively). Multiple logistic regression analysis showed HT was independently associated with HMCAS (adjusted OR/95% CI/ p = 2.762/1.571–4.854/ p  < .001) and admission NIHSS score (adjusted OR/95% CI/ p = 1.081/1.026–1.139/0.003). And HMCAS with HT was independently associated with length of HMCAS (adjusted OR/95% CI/ p = 1.216/1.076–1.374/0.002). Conclusions HMCAS in patients with a large cerebral infarction without thrombolytic therapy is an independent biomarker of HT. Length of HMCAS is also a marker of HT with lower ASPECTS in HMCAS patients.