The photovoltaic (PV) modules are in PV arrays normally connected in series and thus some of them are exposed to high system voltages since frames of the PV modules are grounded. To predict the long-term PV system energy output and PV module lifetime, it is very important to understand and take into account the degradation process of PV modules under high-voltage stress. Accelerated tests under damp heat (over 1300 h of DH85/60; RH = 85%, T = 60 °C) of in-house developed monocrystalline silicon PV modules with p-type solar cells were preformed while connected to a positive or negative voltage bias of 1000 V. The negative biased modules exhibited just a little degradation, while the positive biased modules degraded rapidly. We identified three degradation mechanisms: cell degradation, silver corrosion, and EVA evaporation. The degradation mechanisms contribute to almost 15% of the performance loss of the 1000 V positive biased modules after more than 1300 h of DH85/60 testing, while the power degradation of the negative biased modules remains below 3%.