Background: Grade 3+ radiation-induced lymphopenia is a frequent biological complication of external beam radiotherapy (RT) in the management of head and neck cancers, likely due to the large irradiated cervical volume. This complication has been shown to be a significant prognostic factor for mortality. The aim of this study is to evaluate the difference in lymphopenia and prognosis between unilateral and bilateral prophylactic lymph node irradiation in head and neck cancers. Methods: This is a retrospective, single center case – control study in patients who received unilateral or bilateral radio chemotherapy for head and neck cancers between 2014 and 2020. Cases (unilateral neck irradiation) were matched to controls (bilateral neck irradiation) according to initial TNM, histology, tumor location, postoperative status. The comparison of the evolution of the lymphocyte count during treatment was evaluated by univariate analysis, as well as the evaluation of the overall survival (OS) and the progression free survival (PFS) between these two groups. Another univariate analysis is used to compare OS and PFS in these two groups between patients who developed Grade 3 or higher lymphopenia during treatment and those who did not. Results: In this retrospective study, 94 patients were analyzed (n = 47 in the RT unilateral group and n = 47 in the RT bilateral group). All patients received concomitant systemic therapy. Median age was 59,3 years in the unilateral group (vs 59 years in the control group). Radiotherapy was given postoperatively in 66% vs 53.2% of patients. Squamous cell carcinoma was the most frequent histological subtype with 93,6% in each RT group. All patients were treated in Intensity modulated radiation therapy (IMRT). Median follow up was 38 months in the case group and 37,6 months in the control group. Biological data from the start of radiotherapy to day 100 posttreatment was available for 90 patients (45 in each group). A linear regression model as a function of time and lymphocyte count estimated a -0.011 G/l decrease in lymphocyte count each day and a higher lymphocyte count with unilateral neck irradiation of 0.16 G/l. This was consistent with a mixed model considering the patient as a random effect. In univariate analysis, the lymphocyte nadir was significantly higher in the unilateral group 0.30 [0.15- 0,42] vs 0.37 [0,26-0.48] p = 0,029, with no significant difference in OS and PFS between these two groups. In each of the two groups, there was no significant difference in OS and PFS according to the presence or absence of grade 3 or higher lymphopenia during the treatment. Conclusions: This study, although retrospective, showed a slight benefit on radiation-induced lymphopenia in the context of unilateral radiotherapy without negative impact on OS and PFS.