Precipitation and temperature biases from a set of Regional Climate Models from the CORDEX initiative have been analyzed with the aim of assessing the extent to which the biases may impact on the climate change signal. The analysis has been performed for the South American CORDEX domain. A large warm bias was found over central Argentina (CARG) for most of the models, mainly in the summer season. Results indicate that the possible origin of this bias is an overestimation of the incoming shortwave radiation, in agreement with an underestimation of the relative humidity at 850 hPa, variable that could be used to diagnose cloudiness. Regarding precipitation, the largest biases were found during summertime over north east of Brazil (NEB), where most of the models overestimate the precipitation, leading to wet biases over that region. This bias agrees with models’ underestimation of both the moisture flux convergence and the relative humidity at lower levels of the atmosphere. This outcome suggests that the generation of more clouds in the models may drive the wet bias over NEB. The climate change signal could be affected by these systematic errors, considering that these biases may not be stationary. For both CARG and NEB regions, models with higher warm biases project higher warming levels, mainly in the summer season. In addition, it was found that these relationships are statistically significant with a confidence level of 95%, pointing out that biases are linearly linked with the climate change signal. For precipitation, the relationship between the biases and the projected precipitation changes are only statistically significant for the NEB region, where models with larger wet biases present the highest positive precipitation changes during the warm season. As in the case of biases, the analysis of the temperature and precipitation projections over some regions of South America suggests that they could be affected by clouds. The results found in this study point out that the analysis of the bias behavior could help in a better interpretation of the climate change signal.