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Background  Preexposure prophylaxis (PrEP) is available as a daily pill for preventing infection with the human immunodeficiency virus (HIV). Innovative methods of administering PrEP systemically or topically are being discussed and developed.    Objective  The objective of our study was to assess attitudes toward different experimental modalities of PrEP administration.    Methods  From April to July 2015, we recruited 1106 HIV-negative men who have sex with men through online social media advertisements and surveyed them about their likelihood of using different PrEP modalities. Participants responded to 5-point Likert-scale items indicating how likely they were to use each of the following PrEP modalities: a daily oral pill, on-demand pills, periodic injection, penile gel (either before or after intercourse), rectal gel (before/after), and rectal suppository (before/after). We used Wilcoxon signed rank tests to determine whether the stated likelihood of using any modality differed from daily oral PrEP. Related items were combined to assess differences in likelihood of use based on tissue or time of administration. Participants also ranked their interest in using each modality, and we used the modified Borda count method to determine consensual rankings.    Results  Most participants indicated they would be somewhat likely or very likely to use PrEP as an on-demand pill (685/1105, 61.99%), daily oral pill (528/1036, 50.97%), injection (575/1091, 52.70%), or penile gel (438/755, 58.01% before intercourse; 408/751, 54.33% after). The stated likelihoods of using on-demand pills (median score 4) and of using a penile gel before intercourse (median 4) were both higher than that of using a daily oral pill (median 4,  P <.001 and  P =.001, respectively). Compared with a daily oral pill, participants reported a significantly lower likelihood of using any of the 4 rectal modalities (Wilcoxon signed rank test, all  P <.001). On 10-point Likert scales created by combining application methods, the reported likelihood of using a penile gel (median 7) was higher than that of using a rectal gel (median 6,  P <.001), which was higher than the likelihood of using a rectal suppository (median 6,  P <.001). The modified Borda count ranked on-demand pills as the most preferred modality. There was no difference in likelihood of use of PrEP (gel or suppository) before or after intercourse.    Conclusions  Participants typically prefer systemic PrEP and are less likely to use a modality that is administered rectally. Although most of these modalities are seen as favorable or neutral, attitudes may change as information about efficacy and application becomes available. Further data on modality preference across risk groups will better inform PrEP development.

Preexposure Prophylaxis Modality Preferences Among Men Who Have Sex With Men and Use Social Media in the United States