Tilapia, a major freshwater fish species cultured in southern China, takes up an important position in the development of China's aquaculture. Salinity differences have been proven to have clear effects on the growth and physiology in tilapia. Relationship exists between the salinity for optimum growth in fish and their iso-osmotic condition. When salinities shift away from the iso-osmotic point, a reduction in fish growth and feed utilization could be due to more energy consumption used for osmoregulation. Temperature is also a key factor affecting feeding and growth in tilapia. Serum insulin-like growth factor I (IGF-I) in fish has been associated with growth and osmoregulation. In the current experiment, based on central composite experimental design and response surface method, 13 experimental runs, each replicated three times, were investigated. The effect of temperature (18-37℃), salinity (0-18) and their interaction on serum IGF-I level, specific growth rate (SGR) and feed efficiency (FE) of GIFT strain Nile tilapia juveniles (Oreochromis niloticus) were studied under laboratory conditions, and the interrelationship between IGF-I to SGR and FE was also investigated. The entire experiment lasted for 8 weeks. The results showed that the linear and quadratic effects of water temperature on serum IGF-I, SGR and FE were statistically significant (P<0.05) and the linear and quadratic effects of salinity on serum IGF-I and SGR were also significant (P<0.05). SGR and FE varied with increasing water temperature and salinity in a curvilinear manner. High temperature and high salinity could hinder the increase of SGR and FE. With the increased level of water temperature, serum IGF-I level increased at the beginning and then decreased when temperature was beyond 30℃; serum IGF-I level was lower around the iso-osmotic point. Serum IGF-I level was positively correlated with fish growth and FE, with the R² being 0.496 and 0.698 (P<0.05), respectively. The results showed the evidence of higher SGR and FE at high serum IGF-I levels in tilapia. The interactive effects of temperature × salinity on serum IGF-I, SGR and FE were nosignificant (P>0.05). Water temperature was more important than salinity in affecting serum IGF-I, SGR and FE. The model equations of SGR, FE and serum IGF-I level using least squares method was obtained, with the R² as high as 0.949, 0.986, 0.984, respectively. These models could be used for practical projection. The optimal temperature/salinity combination was obtained utilizing statistical optimization approach: 28.5℃/8.4, at which the maximal SGR and FE reached 2.29%·d^-1 and 0.82, respectively, with the desirability being 0.937. Growth performance of Nile tilapia seemed to be related to the amount of energy expended for osmoregulation. When temperature-salinity deviated from the optimal combination, Nile tilapia has to potentially spend more energy on osmoregulation. These results suggest that the optimum combination of temperature and salinity enhance tilapia growth performance, feeding efficiency and increase serum IGF-I levels.