Acetaminophen has long been assumed to selectively alleviate physical pain, but recent research has started to reveal its broader psychological effects. Building on this work, we find suggestive evidence that acetaminophen affects the basic social process of trust across a national survey and five lab experiments. In a national community sample (MIDUS II), acetaminophen usage was negatively associated with neighborhood trust and feelings of social integration. In a series of lab experiments (N = 767), acetaminophen reduced the influence of self-generated expectations on investments in a trust game. When we manipulated trust game investor expectations, acetaminophen increased investments regardless of expectations. These results provide the first demonstration that an over-the-counter drug can impact trust-related behavior. Overall, the findings paint a complex picture of how situational factors may influence drug effects.