Strike-slip faults in the forearc region of a subduction zone often present significant seismic hazard because of their proximity to population centers. We explore the interaction between thrust events on the subduction interface and strike-slip faults within the forearc region using three-dimensional models of static Coulomb stress change. Model results reveal that subduction earthquakes with slip vectors subparallel to the trench axis enhance the Coulomb stress on strike-slip faults adjacent to the trench but reduce the stress on faults farther back in the forearc region. In contrast, subduction events with slip vectors perpendicular to the trench axis enhance the Coulomb stress on strike-slip faults farther back in the forearc, while reducing the stress adjacent to the trench. A significant contribution to Coulomb stress increase on strike-slip faults in the back region of the forearc comes from “unclamping” of the fault, i.e., reduction in normal stress due to thrust motion on the subduction interface. We argue that although Coulomb stress changes from individual subduction earthquakes are ephemeral, their cumulative effects on the pattern of lithosphere deformation in the forearc region are significant. We use the Coulomb stress models to explain the contrasting deformation pattern between two adjacent segments of the Caribbean subduction zone. Subduction earthquakes with slip vectors nearly perpendicular to the Caribbean trench axis is dominant in the Hispaniola segment, where the strike-slip faults are more than 60 km inland from the trench. In contrast, subduction slip motion is nearly parallel to the Caribbean trench axis along the Puerto Rico segment, where the strike-slip fault is less than 15 km from the trench. This observed jump from a strike-slip fault close to the trench axis in the Puerto Rico segment to the inland faults in Hispaniola is explained by different distributions of Coulomb stress in the forearc region of the two segments, as a result of the change from the nearly trench parallel slip on the Puerto Rico subduction interface to the more perpendicular subduction slip beneath Hispaniola. The observations and modeling suggest that subduction-induced strike-slip seismic hazard to Puerto Rico may be smaller than previously assumed but the hazard to Hispaniola remains high.