Background The composition of the thrombus influences its retrievability by mechanical thrombectomy. Purpose Our study aimed to report on thrombi resistant to aspiration, regarding susceptibility vessel sign and histologic composition. Methods This observational study was based on a prospective database of acute anterior circulation ischemic strokes treated by mechanical thrombectomy. Endovascular first-line strategy was aspiration and in case of failure, combined therapy-rescue was performed. The positivity of susceptibility vessel sign (SVS+) or its negativity (SVS−) was assessed on T2* sequences. The thrombus composition was analyzed with hematoxylin eosin staining. Results Histological analysis was performed on 102 clots. Thrombi with SVS− were significantly richer in fibrin/platelets, p = 0.04. Out of 210 mechanical thrombectomy, aspiration first pass strategy was performed in 131/210 (62%) patients. Combined therapy-rescue was needed in 37% of aspiration first pass strategy cases ( n = 131). Clots retrieved combined therapy-rescue were richer in fibrin/platelets 63.9% versus 50.8% for aspiration first pass strategy, p = 0.03. Logistic regression analysis showed that fibrin/platelet-poor clots (<60%) were significantly more likely to be recanalized by aspiration first pass strategy compared to fibrin/platelet-rich clots (>60%) that were more likely recanalized by combined therapy-rescue after aspiration first pass strategy failure (OR = 3.5; 95% CI = 1.2–10.8; p = 0.0054). Conclusions Our results confirm that SVS− clots are rich in fibrin/platelets and suggest that these “white clots” are less likely to be retrieved by aspiration alone and more often require the use of combined therapy.