Abstract Purpose To evaluate the pathological complete response (pCR) rate of locally advanced rectal cancer (LARC) after adaptive high-dose neoadjuvant chemoradiation (CRT) based on ¹⁸ F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸ F-FDG-PET/CT). Methods The primary endpoint was the pCR rate. Secondary endpoints were the predictive value of ¹⁸ F-FDG-PET/CT on pathological response and acute and late toxicity. All patients performed ¹⁸ F-FDG-PET/CT at baseline (PET₀) and after 2 weeks during CRT (PET₁). The metabolic PET parameters were calculated both at the PET₀ and PET₁. The total CRT dose was 45 Gy to the pelvic lymph nodes and 50 Gy to the primary tumor, corresponding mesorectum, and to metastatic lymph nodes. Furthermore, a sequential boost was delivered to a biological target volume defined by PET₁ with an additional dose of 5 Gy in 2 fractions. Capecitabine (825 mg/m² twice daily orally) was prescribed for the entire treatment duration. Results Eighteen patients (13 males, 5 females; median age 55 years [range, 41–77 years]) were enrolled in the trial. Patients underwent surgical resection at 8–9 weeks after the end of neoadjuvant CRT. No patient showed grade > 1 acute radiation-induced toxicity. Seven patients (38.8%) had TRG = 0 (complete regression), 5 (27.0%) showed TRG = 2, and 6 (33.0%) had TRG = 3. Based on the TRG results, patients were classified in two groups: TRG = 0 (pCR) and TRG = 1, 2, 3 (non pCR). Accepting p < 0.05 as the level of significance, at the Kruskal–Wallis test, the medians of baseline-MTV, interim-SUVmax, interim-SUVmean, interim-MTV, interim-TLG, and the MTV reduction were significantly different between the two groups. ¹⁸ F-FDG-PET/CT was able to predict the pCR in 77.8% of cases through compared evaluation of both baseline PET/CT and interim PET/CT. Conclusions Our results showed that a dose escalation on a reduced target in the final phase of CRT is well tolerated and able to provide a high pCR rate.