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Background  Hookah tobacco smoking (HTS) is a particularly important issue for public health professionals to address owing to its prevalence and deleterious health effects. Social media sites can be a valuable tool for public health officials to conduct informational health campaigns. Current social media platforms provide researchers with opportunities to better identify and target specific audiences and even individuals. However, we are not aware of systematic research attempting to identify audiences with mixed or ambivalent views toward HTS.    Objective  The objective of this study was to (1) confirm previous research showing positively skewed HTS sentiment on Twitter using a larger dataset by leveraging machine learning techniques and (2) systematically identify individuals who exhibit mixed opinions about HTS via the Twitter platform and therefore represent key audiences for intervention.    Methods  We prospectively collected tweets related to HTS from January to June 2016. We double-coded sentiment for a subset of approximately 5000 randomly sampled tweets for sentiment toward HTS and used these data to train a machine learning classifier to assess the remaining approximately 556,000 HTS-related Twitter posts. Natural language processing software was used to extract linguistic  features  (ie, language-based covariates). The data were processed by machine learning tools and algorithms using R. Finally, we used the results to identify individuals who, because they had consistently posted both positive and negative content, might be ambivalent toward HTS and represent an ideal audience for intervention.    Results  There were 561,960 HTS-related tweets: 373,911 were classified as positive and 183,139 were classified as negative. A set of 12,861 users met a priori criteria indicating that they posted both positive and negative tweets about HTS.    Conclusions  Sentiment analysis can allow researchers to identify audience segments on social media that demonstrate ambiguity toward key public health issues, such as HTS, and therefore represent ideal populations for intervention. Using large social media datasets can help public health officials to preemptively identify specific audience segments that would be most receptive to targeted campaigns.

Identifying Key Target Audiences for Public Health Campaigns: Leveraging Machine Learning in the Case of Hookah Tobacco Smoking