Background: In HPV-primary screening, sample quality significantly influences test accuracy. Unlike cytology-based screening, no consensus guidelines exist for sample quality assessment in HPV testing. This study aims to evaluate the impact of sample cellularity on HPV testing. Methods: A total of 37,592 liquid-based cytology (LBC) samples from women undergoing screening (aged 30-64, mean 47.8±9 years) were analyzed using Cobas®4800 HPV Test (Roche). Sample adequacy was assessed by the assay’s β-globin internal control and by an independent quantitative cellularity assessment (OncoPredict HPV, Hiantis). HPV positivity rates (PR) were stratified according to β-globin Ct values. Results: Overall HPV-PR was 7.7%. PR reached 9.7% in samples with β-globin ≤ 28Ct, decreasing markedly to 1.4% for β-globin > 34 Ct (p < 0.001). Quantitative analysis showed that Cobas®4800 β-globin Ct = 34 corresponds to approximately 1,5x10^3 nucleated cells/rxn. A subset of 195 HPV-negative samples with β-globin Ct ≥34 was evaluated by LBC: 19% had inadequate cellularity according to LBC guidelines, 8% ≥ ASC-US and 73% NILMs, of which 65% showed cellular atrophy. Conclusion: These findings emphasize the importance of assessing cellularity in HPV-screening in order to avoid potentially false-negative results due to inadequate samples. Future research should focus on establishing standardized cellularity thresholds to improve screening accuracy.