PURPOSE/OBJECTIVE(S): Intensity modulated Radiation Therapy (IMRT) is now considered standard of care for patients with head and neck (HN) cancer. However, it was only introduced into the clinic two decades ago. In 2001 the RTOG opened the first clinical trial evaluating IMRT for HN cancer in a multi-institution setting. The primary endpoints of acceptable 2-year local-regional control and reduction in acute xerostomia were met and reported previously. This report highlights additional secondary endpoints including late toxicities and long-term disease control and survival outcomes. MATERIALS/METHODS: Eligibility was patients diagnosed with T1-2, N0-1 oropharyngeal cancer (AJCC v5). The primary objective was to determine if IMRT yielded a relative reduction, compared to historical control, in acute xerostomia of at least 35% while maintaining an acceptable rate of local-regional failure at 2 years less than 20%. Secondary endpoints included late toxicities graded by RTOG/EORTC criteria and are reported with descriptive statistics, disease control and survival outcomes. Local-regional failure rates were estimated by the cumulative incidence method, and disease-free and overall survival rates estimated with the Kaplan-Meier method. RESULTS: Sixty-seven of 69 patients enrolled (between 2001 and 2005) were analyzed. Fifty patients (75%) had T2 disease and 38 (57%) were N0. The highest reported late (> 90 days after start of radiation therapy) toxicities were: grade 5 (0%), grade 4 (9%), grade 3 (13%), and grade 2 (63%). Grade 3-4 toxicities included mucous membranes (7%), bone (4%), esophagus (4%), salivary gland (4%), pain (3%), weight loss (1%), and hemorrhage (1%). Grade 2-3 salivary gland toxicity was reported in 70%. Tinnitus was reported by 18% of patients, and 39% reported hearing loss. The median follow-up for surviving patients was 11.9 years. The estimated 10-year overall survival, disease-free survival, and local-regional failure rates were 67% (95% CI 55-78%), 50% (95% CI 38-62%) and 15% [95% confidence interval (CI) 8-25%], respectively. Only 15% of deaths were attributed to the index cancer under study. CONCLUSION: NRG/RTOG 0022 was the first trial testing the feasibility of IMRT in a multi-institutional setting. In addition to meeting the criteria for acceptable local-regional control and reduction in acute xerostomia, long-term outcomes were very good with few deaths attributed to the studied cancer, 2/3 of patients alive at 10 years, and few grade 3-4 toxicities. Since conduct of this study, further improvements in IMRT have been accomplished both with regards to technical advancements in treatment delivery as well as attention to additional avoidance structures beyond the parotid glands. IMRT has transitioned from an optional form of radiation to the expected radiation technique to be delivered in RTOG/NRG Oncology trials of HN cancer.