Few studies with a limited number of patients focused on the outcomes of patients with diffusion-weighted imaging (DWI)-negative acute ischemic stroke (AIS) after intravenous thrombolysis (IVT) and/or endovascular treatment (EVT). This retrospective observational, single-center study included all consecutive patients admitted for AIS involving the anterior circulation and treated with IVT and/or EVT between January 1, 2015 and December 31, 2023. The collected data were used to identify the characteristics of patients with negative DWI and to compare outcomes in patients with negative and positive DWI. Among the 1210 patients included, 47 (3.9%) had negative (DWI-negative group) and 1163 had increased DWI signal (DWI-positive group). In the DWI-negative group, the mean age was 69 years (SD=19.4), 55.3% were men, and 27 (57.4%) had a large vessel occlusion. Thirty eight (80.9%) were treated with IVT alone, 7 (14.9%) with EVT alone, and 2 (4.3%) with both. Fluid attenuated inversion recovery (FLAIR) sequences were the most sensitive to detect predictive factors of cerebral ischemia, such as vessel thrombosis and the spaghetti sign that were found in 68.1% and 83%, of patients, respectively. Oxyhemoglobin-sensitive (T2*) and susceptibility-weighted angiography (SWAN) sequences were less sensitive: vessel thrombosis and the brush sign were detected in 55.3% and 19.1% of patients, respectively. Comparison of the two DWI groups showed that M2 occlusion was more frequent (31.9% vs 13%, p<0.001) and M1 occlusion rarer (19.1% vs 36%, p<0.02) in the DWI-negative than DWI-positive group. At admission, the median National Institutes of Health Stroke Scale score was lower in the DWI-negative than DWI-positive group (2 vs 6, p=0.0001), but the median symptom onset-to-MRI time was similar in both groups (108 vs 111 min, p=0.88). In patients with DWI-negative AIS, symptoms are less severe. Large vessel occlusions, notably in the M2 segment, are more distal at the expense of the M1 segment of MCA. The spaghetti sign remains the most predictive feature of AIS that should be specifically searched in the absence of DWI lesions.