The extreme wind pressure might lead to local or overall structural failures. The physical mechanisms behind extreme pressures on two tandem square cylinders are investigated using large-eddy simulation at a Reynolds number of 8 × 104. The spacing ratio P/B ranges from 1.1 to 5 (P: cylinders’ center distance; B: side length). The aerodynamic coefficients, flow patterns, mean and fluctuating pressure coefficients, pressure skewness and kurtosis, and instantaneous flow structures are analyzed. The extreme negative pressures are induced by the intermittent appearance of strong vortices attached to the cylinder surfaces. “Gap vortex” and “wall vortex” are responsible for the extreme pressure at the gap-sides of two cylinders in the single mode (1 < P/B < 2). “Corner vortex” would cause extreme negative pressure near the front corners of the upstream cylinder and the rear corners of both cylinders at most spacings. At the reattached (2 ≤ P/B < 4) and binary (4 ≤ P/B ≤ 5) modes, the Karman vortex released from the rear corner of the downstream cylinders leads to extreme pressure on the rear surface. As the spacing increases, the extreme pressure on non-Gaussian-pressure regions is generally strengthened but the three-dimensionality in vortex structures and instantaneous pressure distributions roughly declines.