Multi-span plastic greenhouses mainly depend on solar heat storage. In winter, greenhouse is closed for prolonged periods for thermal insulation to avoid indoor heat being lost. Therefore, this would lead to indoor high humidity and consequently the occurrence of crop diseases. For making a good compromise between dehumidification effectiveness and indoor heat loss prevention, a full-scale computational fluid dynamics (CFD) model was developed based on an 11-span plastic greenhouse. Firstly, the model was validated by comparing experimental humidity with CFD simulations under roof ventilation. CFD simulations had similar trends to those of the experiments, with less than 5% difference. Then, the validated model was used to investigate the influences of vent configurations (i.e. side, roof and side plus roof) on the airflow pattern and humidity field inside the greenhouse. Simulations showed that roof ventilation tended to be the best. With the roof ventilation, dehumidification in the crop canopy could be achieved in 3 min. After dehumidification, relative humidity was reduced from 92% to 68% and indoor humidity homogeneity was good. Moreover, responding heat loss was less. Therefore, this ventilation mode is able to meet the requirements of thermal insulation and dehumidification under winter climate conditions.