Much concern has been raised about the power of political microtargeting to sway voters’ opinions, influence elections, and undermine democracy. Yet little research has directly estimated the persuasive advantage of microtargeting over alternative campaign strategies. Here, we do so using two studies focused on U.S. policy issue advertising. To implement a microtargeting strategy, we combined machine learning with message pretesting to determine which advertisements to show to which individuals to maximize persuasive impact. Using survey experiments, we then compared the performance of this microtargeting strategy against two other messaging strategies. Overall, we estimate that our microtargeting strategy outperformed these strategies by an average of 70% or more in a context where all of the messages aimed to influence the same policy attitude (Study 1). Notably, however, we found no evidence that targeting messages by more than one covariate yielded additional persuasive gains, and the performance advantage of microtargeting was primarily visible for one of the two policy issues under study. Moreover, when microtargeting was used instead to identify which policy attitudes to target with messaging (Study 2), its advantage was more limited. Taken together, these results suggest that the use of microtargeting—combining message pretesting with machine learning—can potentially increase campaigns’ persuasive influence and may not require the collection of vast amounts of personal data to uncover complex interactions between audience characteristics and political messaging. However, the extent to which this approach confers a persuasive advantage over alternative strategies likely depends heavily on context.