This work aimed to evaluate the effects of using three different substrates in the semi-hydroponic culture of lettuce (Lactuca sativa L.) using two different nutrient solutions. A first trial was performed with a nutrient solution rich in macronutrients and micronutrients suitable for lettuce culture, and a second trial with a nutrient solution with pretreated wastewater from effluents of a cheese factory. The experimental design was in randomized blocks with three repetitions and three substrates were used: perlite, coconut fiber, and expanded clay, in both trials. The following parameters were observed: number of leaves, diameter of the cabbage, fresh and dry weight of the aerial part, chlorophyll index and mineral composition of the lettuce. For the first trial, the highest result for the number of leaves (20 leaves), fresh weight (142.0 g) and dry weight (7.2 g) of the aerial part was obtained in the plants growing on perlite. In the second trial, the highest result for the number of leaves (28 leaves), diameter of cabbage (26.7 cm), fresh weight (118.8 g) and dry weight (9.5 g) of the aerial part were achieved by the plants that were grown in coconut fiber. The nutrient solutions were analyzed after each irrigation cycle to verify the possibility of their discharge into the environment. Several parameters were analyzed: pH, conductivity, redox potential, nitrates, nitrites, ammoniacal nitrogen, chlorides, hardness, calcium, phosphates, sodium, potassium, chemical oxygen demand (COD) and magnesium. Ammoniacal nitrogen was found to be the only nutrient that can limits the discharge of nutrient solutions into the environment. It was also proven that the plants, besides obtaining the nutrients necessary for their development in the semi-hydroponic system with the nutrient solution with pre-treated residual water, also functioned as a purification system, allowing the said nutrient solution to be discharged into the environment at the end of each cycle.