Background: Trials in human papilloma virus associated oropharyngeal squamous cell carcinoma (HPVOPSCC), substituting cetuximab (CETUX) for cisplatin (CIS) with radiotherapy (RT), resulted in decreased efficacy without improved toxicity or symptom burden. We reported that high intratumoral immune cell (ITIC) CD103 expression (> 30%), a marker of tissue-resident memory T cells, is associated with better prognosis in unselected patients with HPVOPSCC treated with CIS/RT. In this study our aim was to determine whether low risk HPVOPSCC patients treated with CETUX/RT with high CD103 have a superior prognosis. Methods: TROG 12.01 and De-ESCALaTE are randomised multicentre trials that compared 70Gy RT/CETUX with 70Gy RT/CIS (weekly in TROG 12.01, 3-weekly in De-ESCALaTE) in patients with HPVOPSCC, low risk by Ang criteria: AJCC 7^th Stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history > 10 pack years and/or distant metastases). In TROG 12.01 T4 and/or N3 patients were also excluded. Eligible patients required tumor samples available for immune cell quantification on immunohistochemistry. Data from the two trials were pooled, with analyses performed in eligible randomised patients who commenced treatment. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/ RT comparing CD103 ITIC > 30% (high) vs. < 30% (low). High/low CD103 were compared using Cox model adjusting for age, stage and trial. Results: Samples for CD103 testing were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. ITIC CD103 expression was high in 26% of patients. The median follow-up was 3.2 years. The 3 -year failure-free survival rates in patients treated with CETUX/RT were 92% (95% CI: 78-97%) in high CD103 and 74% (95% CI: 64-82%) in low CD103, adjusted HR 0.25 (95% CI: 0.14-0.44); p < 0.001. The 3 -year overall survival (OS) in patients treated with CETUX/RT were 100% in high CD103 and 86% (95% CI: 76-92%) in low CD103, p < 0.001. Superior FFS in the high CD103 group was independent of stage. In patients treated with CIS/RT there was no significant difference in FFS (3-year 86% in high CD103 and 90% in low CD103; p = 0.55) or in OS (3-year 100% in high CD103 and 95% in low CD103; p = 0.14). The increase in failures in the low CD103 patients treated with CETUX/RT was evenly split between distant and locoregional failures. Conclusions: ITIC CD103 separates CETUX/RT treated low risk HPVOPSCC into excellent and poor prognosis subgroups. In a low risk population CIS/RT achieves excellent outcomes in both high and low ITIC CD103 groups. The high ITIC CD103 population is a rational target for future de-intensification trials.