The interest in unethical behavior in organizations has grown over the past decades as ethical scandals have become mainstream. However, research on how organizational practices may prevent these behaviors is still scarce, particularly for those behaviors that are unethical but also benefit the organization. Across two studies guided by Uncertainty Reduction Theory, we examine the relationship between high-performance work systems and unethical pro-organizational behavior via perceptions of politics. In study 1 (N = 244), we found support for the indirect effect using a time-lagged design. In study 2 (N = 809), we confirmed our mediation hypothesis using unethical pro-organizational behaviors rated by the supervisor and reiterated the role played by perceptions of politics, by ruling out job insecurity as a second potential uncertainty reduction mechanism. Taken together, these findings have important theoretical and practical implications as they consistently demonstrate that high-performance work systems reduce uncertainty regarding the internal functioning of the organization (reflected in perceptions of politics), and by doing so, decrease the extent to which employees engage in unethical behaviors in favor of the organization.