PURPOSE Lymphopenia is associated with poor survival outcomes in head and neck squamous cell carcinoma (HNSCC), yet there is no consensus on whether we should limit lymphopenia risks during treatment. To fully elucidate the prognostic role of baseline versus treatment-related lymphopenia, a robust analysis is necessary to investigate the relative importance of various lymphopenia metrics (LMs) in predicting survival outcomes. METHODS In this prospective cohort study, 363 patients were eligible for analysis (patients with newly diagnosed, nonmetastatic HNSCC treated with neck radiation with or without chemotherapy in 2015-2019). Data were acquired on 28 covariates: seven baseline, five disease, seven treatment, and nine LMs, including static and time-varying features for absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio, and immature granulocytes (IGs). IGs were included, given their hypothesized role in inhibiting lymphocyte function. Overall, there were 4.0% missing data. Median follow-up was 2.9 years. We developed a model (POTOMAC) to predict survival outcomes using a random survival forest (RSF) procedure. RSF uses an ensemble approach to reduce the risk of overfitting and provides internal validation of the model using data that are not used in model development. The ability to predict survival risk was assessed using the AUC for the predicted risk score. RESULTS POTOMAC predicted 2-year survival with AUCs at 0.78 for overall survival (primary end point) and 0.73 for progression-free survival (secondary end point). Top modifiable risk factors included radiation dose and max ALC decrease. Top baseline risk factors included age, Charlson Comorbidity Index, Karnofsky Performance Score, and baseline IGs. Top-ranking LMs had superior prognostic performance when compared with human papillomavirus status, chemotherapy type, and dose (up to 2, 8, and 65 times higher in variable importance score). CONCLUSION POTOMAC provides important insights into potential approaches to reduce mortality in patients with HNSCC treated by chemoradiation but needs to be validated in future studies.