AbstractEarly acquired resistance (EAR) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in lung adenocarcinomas before radiographic advance cannot be perceived by the naked eye. This study aimed to discover and validate a CT radiomic model to precisely identify the EAR. Training cohort (n = 67) and internal test cohort (n = 29) were from the First Affiliated Hospital of Fujian Medical University, and external test cohort (n = 29) was from the Second Affiliated Hospital of Xiamen Medical College. Follow-up CT images at three different times of each patient were collected: (1) baseline images before EGFR-TKIs therapy; (2) first follow-up images after EGFR-TKIs therapy (FFT); (3) EAR images, which were the last follow-up images before radiographic advance. The features extracted from FFT and EAR were used to construct the classic radiomic model. The delta features which were calculated by subtracting the baseline from either FFT or EAR were used to construct the delta radiomic model. The classic radiomic model achieved AUC 0.682 and 0.641 in training and internal test cohorts, respectively. The delta radiomic model achieved AUC 0.730 and 0.704 in training and internal test cohorts, respectively. Over the external test cohort, the delta radiomic model achieved AUC 0.661. The decision curve analysis showed that when threshold of the probability of the EAR to the EGFR-TKIs was between 0.3 and 0.82, the proposed model was more benefit than treating all patients. Based on two central studies, the delta radiomic model derived from the follow-up non-enhanced CT images can help clinicians to identify the EAR to EGFR-TKIs in lung adenocarcinomas before radiographic advance and optimize clinical outcomes.