On the 4 February 2019, the Western Cape Department of Health's Facebook page announced the implementation of a school-based vaccination campaign aimed to administer the first doses of human papillomavirus (HPV) vaccine in public schools to Grade 4 girls who are nine years old. This announcement was met with a flurry of social media responses posted on the campaign's Facebook page. This study identifies determinants of vaccine hesitancy amongst responses provided by social media users to this post. On 8 March 2019, we conducted a qualitative study including all 157 comments to the Facebook post. The post had 659 'emotion' reactions: 574 "likes", 62 "loves", 21 "angry faces", 2 "laughs", 2 "wows" and 1 "sad face". An overwhelming majority (636/659 i.e. 97%) of reactions were favourable to the HPV vaccination campaign. Out of the 157 comments, we judged 52 (33%) of them to be 'hesitant', suggesting that people with negative reactions though few in number, were more likely to be vocal deniers. Concern around the safety of HPV vaccines including effects on reproductive health was the most common theme identified. Other emerging themes included: risk of cervical cancer perceived as being low, issues around consent, concerns that girls are being used for research, questionable vaccine effectiveness, use of the school-based strategy for the campaign, risk-benefits calculations of HPV vaccination and constraints such as stock-outs. Knowing someone who had been affected or being at risk of cervical cancer, having knowledge about the causes of cervical cancer, confidence in the effectiveness and safety of the vaccine, knowing the vaccine was being used in high income settings, and having strong recommendations from the World Health Organisation and key actors seemed to increase the willingness to accept the vaccine. The magnitude and causes of HPV vaccine hesitancy need to be investigated to ensure the success of this programme.