Purpose <p>To evaluate the safety and effectiveness of a nurse-led telephone triage clinic, utilising the Head and Neck Cancer Risk Calculator version 2 (HaNC-RC-v2) with consultant oversight, for patients referred on the UK two-week wait (2WW) pathway for suspected head and neck cancer.</p> Methods <p>A prospective service evaluation was conducted in a UK hospital receiving ~ 5000 2WW referrals annually. Between November 2023 and March 2025, 2,556 patients underwent telephone triage. Patients scoring ≥ 2.2% on HaNC-RC-v2 remained on the 2WW pathway; those scoring &lt; 2.2% were considered for downgrade to a 6-week review following consultant review of their case. Patients referred with an investigation showing a thyroid nodule suspicious for malignancy were sent straight-to-test for ultrasound-guided biopsy. Diagnostic performance was assessed using histologically confirmed malignancy as the reference standard.</p> Results <p>Of 2,556 triaged patients, 67 (2.6%) had cancer. At the 2.2% cut-off, 16.6% (424/2556) were downgraded, with 3 cancers later diagnosed (0.7%; 3/424). The overall negative predictive value was 99.3% with overall potential harm in 0.12% of all referrals. The straight-to-test pathway diagnosed 14 thyroid cancers (11.6%; 14/121) with shorter mean time to diagnosis (45.3 vs. 56.5 days).</p> Conclusion <p>A nurse-led telephone triage clinic using HaNC-RC-v2 safely downgraded low-risk patients with minimal harm while maintaining a high negative predictive value. Incorporating straight-to-test improved cancer detection and expedited diagnosis. This pathway may enhance service efficiency in managing the increasing volume of suspected cancer referrals across various healthcare systems.</p>