Low pressure chemical vapor deposition (LPCVD) is one of the most important processes during semiconductor manufacturing. However, the spatial distribution of internal temperature and extremely few samples makes it hard to build a good-quality model of this batch process. Besides, due to the properties of this process, the reliability of the model must be taken into consideration when optimizing the MVs. In this work, an optimal design strategy based on the self-learning Gaussian process model (GPM) is proposed to control this kind of spatial batch process. The GPM is utilized as the internal model to predict the thicknesses of thin films on all spatial-distributed wafers using the limited data. Unlike the conventional model based design, the uncertainties of predictions provided by GPM are taken into consideration to guide the optimal design of manipulated variables so that the designing can be more prudent. Besides, the GPM is also actively enhanced using as little data as possible based on the predictive uncertainties. The effectiveness of the proposed strategy is successfully demonstrated in an LPCVD process. (C) 2015 The Chemical Industry and Engineering Society of China, and Chemical Industry Press. All rights reserved.