The inherent anisotropy of composites complicates their damage response. The influence of multiaxiality, particularly in carbon-based composites, is not thoroughly understood due to obstacles related to damage monitoring during loading. In this study, the response of different carbon/epoxy laminates under fatigue is examined through dedicated in situ microscopic observations. By varying the orientation of off-axis layers, the impact of multiaxiality on the mechanical and damage response is evaluated. Furthermore, balanced and unbalanced laminates are compared, considering the limited information for the latter. The influence of the number of off-axis layers is finally assessed leading to important conclusions about optimal fatigue response. The fatigue response is evaluated in all cases considering both the mechanical properties and the damage characteristics. Significant conclusions are drawn, especially for the benefits of unbalanced laminates and the impact of shear stresses, allowing for the utilization of the obtained data as important input for the establishment of reliable fatigue damage models.