Tonsillar squamous cell carcinoma (TSCC) is frequently associated with human papillomavirus (HPV) and chromosome instability. Data from cellular model systems are, however, controversial concerning a relation between HPV and chromosome instability development. Here we studied this association in 77 primary TSCC with known clinical outcome and cell cycle protein expression profiles. Thirty‐two tumors (42%) showed HPV16‐integration. All 77 cases were analyzed by fluorescence in situ hybridization using chromosome 1‐ and 7‐specific centromere DNA probes to detect chromosome instability, indicated by the presence of chromosome imbalances and/or polyploidization for these chromosomes. In addition, eight HPV‐positive dysplasias, seven of which were adjacent to a carcinoma, were analyzed. Disomy for chromosome 1 and 7 was present in 29 out of 77 TSCC (38%), of which 19 were HPV16‐positive (p = 0.002). Aneusomy was observed in the remaining 48 TSCC, of which 13 were HPV‐positive. Aneusomies correlated significantly with tobacco‐ and alcohol consumption (p = 0.001 and p = 0.016, respectively) and a higher T‐stage (p = 0.018). Both HPV‐positivity and chromosome disomy were significantly associated with a favorable disease‐free survival (p = 0.001 and p = 0.025, respectively). Particularly in the HPV16‐positive group chromosome instability is a very strong indicator for an unfavorable prognosis (p = 0.032). In the dysplasias an identical HPV and chromosome copy number status was identified as in the adjacent tumors. We conclude that HPV‐positive TSCC and their precursor lesions are more often genetically stable than HPV‐negative lesions and that these tumors are associated with a favorable prognosis. Chromosome instability is an indicator for unfavorable prognosis, particularly in the HPV‐positive patient group. What's new? While tonsillar squamous cell carcinoma (TSCC) frequently is associated with human papillomavirus (HPV) and chromosome instability, data have been based primarily on in vitro cell model experiments. In this study, which examined tissue samples from patients with primary TSCC, HPV‐positive tumors were found to have comparatively stable genomes. Chromosome instability in these tumors was correlated with unfavorable prognosis. The findings could have clinical implications for TSCC.