Growing medium and fertilization are the most effective methods for controlling and improving the vegetative growth characteristics, head quality, yield and nutritional value of lettuce. Therefore the aim of this study was to determine the effect of different growing media when using organic or inorganic fertilization that associated with closed system on lettuce production in soilless culture system. Planting was conducted on A- shape system under unheated plastic greenhouse conditions. Experimental treatments included two nutrient solutions (mineral nutrient and compost tea) and seven substrates i.e. Peat moss, Perlite, Coir, Rice straw, Compost, Peat moss + Perlite  (1:1 v:v) and Coir + Perlite (1:1 v:v). Results revealed that mineral fertilizer had better mean values for all measured vegetative growth parameters, total yield, NPK and chlorophyll content compared with organic fertilizer. The best vegetative growth characters in terms of leaf length, width, and area, number of leaves, head firmness, surround and weight, total yield, NPK and chlorophyll contents were occurred 100 % in coir or peat. The most favorable beneficial interaction treatments regarding the previous growth characters were produced in plants which planted in coir or peat moss with mineral fertilizers. The results indicated that lettuce plants on the peat moss substrate with organic solution grew healthier, but the heads were small and the yield was decreased compared with the inorganic solution. The study revealed that, differences in nutrient fertilizers and growing substrates were significant and their influences have affected the growth and yield of lettuce when cultivated under controlled environment. This study showed that mineral fertilizer had better mean values for all measured growth parameters. While, peat moss and coir substrates proved to be the best growing for lettuce. This growing media enable the roots to develop better. Thus paving the way for plants to absorb more nutrients than the plants grown in other different substrates.