Fish skin gelatin was hydrolyzed with papain to produce antioxidant peptides. Response surface methodology (RSM) was applied to optimize the hydrolysis conditions (including enzyme to substrate ratio [E/S], hydrolysis time, and temperature). The highest degree of hydrolysis (DH) (50.1 +/- 1.1%) was obtained at an E/S of 2% at 56.8 degrees C, 2.11 h, and was not significantly different from the predicted values within a 95% confidence interval. The highest 1,1-diphenyl-2-picrylhydrazyl (DPPH) (96.8 +/- 0.9%) and 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS(+)) (9.80 +/- 0.11 mM Trolox [6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid]) radical-scavenging activities of fish gelatin hydrolyzates were obtained at an E/S of 3% at 52.1 degrees C, 2.65 h, and both DPPH and ABTS(+) radical-scavenging activities were not significantly different from the predicted values 97.3% and 9.86 mM Trolox within the 95% confidence interval. Therefore, RSM is an efficient way to optimize fish gelatin hydrolysation and the resultant hydrolyzates show promise as antioxidant peptides. Practical Application: There is a growing interest in the use of fish gelatin as an alternative to mammalian gelatin. One potential use is as a source of widely acceptable functional compounds. In this study, a search for antioxidant peptides from fish gelatin prepared by an enzymatic method has been successfully done. This suggests that this is a practical way to obtain bioactive peptides.