Colorectal laterally spreading tumors (LSTs) with malignant potential require en bloc resection by endoscopic submucosal dissection (ESD), but lesions with deep submucosal invasion (SMI) are endoscopically unresectable.To investigate the factors associated with high-grade dysplasia (HGD)/carcinoma and deep SMI in colorectal LSTs.The endoscopic and histological results of consecutive patients who underwent ESD for colorectal LSTs in our hospital from June 2013 to March 2019 were retrospectively analyzed. The characteristics of LST subtypes were compared. Risk factors for HGD/carcinoma and deep SMI (invasion depth ≥ 1000 μm) were determined using multivariate logistic regression.A total of 323 patients with 341 colorectal LSTs were enrolled. Among the four subtypes, non-granular pseudodepressed (NG-PD) LSTs (85.5%) had the highest rate of HGD/carcinoma, followed by the granular nodular mixed (G-NM) (77.0%), granular homogenous (29.5%), and non-granular flat elevated (24.2%) subtypes. Deep SMI occurred commonly in NG-PD LSTs (12.9%). In the adjusted multivariate analysis, NG-PD [odds ratio (OR) = 16.8, P < 0.001) and G-NM (OR = 7.8, P < 0.001) subtypes, size ≥ 2 cm (OR = 2.2, P = 0.005), and positive non-lifting sign (OR = 3.3, P = 0.024) were independently associated with HGD/carcinoma. The NG-PD subtype (OR = 13.3, P < 0.001) and rectosigmoid location (OR = 8.7, P = 0.007) were independent risk factors for deep SMI.Because of their increased risk for malignancy, it is highly recommended that NG-PD and G-NM LSTs are removed en bloc through ESD. Given their substantial risk for deep SMI, surgery needs to be considered for NG-PD LSTs located in the rectosigmoid, especially those with positive non-lifting signs.©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.