Background: In the weekly-3-weekly (W3W) study, cisplatin at 100 mg/m² once-every-3-weeks led to superior locoregional control compared to cisplatin 30 mg/m² once-a-week in combination with radical radiation for locally advanced head and neck squamous cell carcinoma (LAHNSCC). We report the updated analysis of the study. Methods: In this phase III open label non-inferiority study conducted between 2013 and 2017, 300 patients with LAHNSCC were randomly assigned to receive cisplatin 100 mg/m² once-in-3-weeks or cisplatin 30 mg/m² once-a-week, concurrently with radiation. The primary endpoint was locoregional control. Secondary outcomes included progression free survival (PFS), overall survival (OS), toxicity, and quality of life. Results: As of February 5, 2022 (median follow-up, 77.3 months), 132 patients (44%) have had an event for locoregional recurrence; 75 (50%) in the once-a-week cisplatin arm and 57 (38%) in the once-every-3-weeks cisplatin arm. The updated estimated cumulative 2-year locoregional control rates were 59.3% and 75.3% in the once-a-week and once-every-3-weeks cisplatin arms, respectively; absolute difference, 16% (95% CI, 7.19 to 24.81). The estimated 5-year locoregional control rates were 48.2% and 55.2% in the once-a-week and once-every-3-weeks cisplatin arms respectively; absolute difference, 7% (95% CI, -2.5 to 16.5). The median time to locoregional failure was 46.1 months (95% CI, 31.63 to 60.56) in the once-a-week cisplatin arm, and 57.9 months (95% CI, 47.1 to 68.6) in the once-every-3-weeks cisplatin arm; HR, 1.43 (95% CI, 1.01 to 2.02); P = 0.042. The estimated median PFS was 17.5 months (95% CI, 0 to 38.31) in the once-a-week cisplatin arm, versus 37.5 months (95% CI, 28.45 to 46.45) in the once-every-3-weeks cisplatin arm; HR, 1.13 (95% CI, 0.85 to 1.5); P = 0.41. Events for OS included 173 (57.7%) deaths; 109 (36.3%) patients are alive, and 18 (6%) are lost to follow-up. The 5-year OS in the once-a-week and once-every-3-weeks cisplatin arms were 43.1% and 48.6%, respectively. Estimated median OS was 38.5 months (95% CI, 16.3 to 60.7) in the once-a-week cisplatin arm, versus 57.3 months (95% CI, 38.6 to 75.9) in the once-every-3-weeks cisplatin arm; HR, 1.19 (95% CI, 0.89 to 1.6); P = 0.238. Details regarding chronic toxicities and second primaries will be presented. Conclusions: Long term follow-up confirms that cisplatin at 100 mg/m² administered once-every-3-weeks concurrently with radical radiation for LAHNSCC leads to superior locoregional control and should remain the standard of care. The study was not powered to test for a difference in OS; OS was numerically higher in the once-every-3-weeks cisplatin arm, but the difference did not attain statistical significance. Clinical trial information: CTRI/2012/10/ 003062.