Cayenne pepper is known as a sensitive plant to water stress, either drought or flooding. However, not many studies on the plant's response to the naturally occurring periodic flooding have been reported to date. This study aimed to determine the agronomic and genetic response of cayenne pepper against periodic flooding and find whether RAPD profile reflects periodic flooding endurance. Three cultivars of cayenne pepper: Cakra Hijau (CH); Mhanu XR (M); and Sret (S) were used. Plants were treated with periodic flooding P0 (one day of flooding followed by two days of drainage), P1 (2 x P0), and P2 (3 x P0), and C as control. A completely randomized design was used for the experiment, and the data obtained were analyzed statistically. Plant height and the number of fruits between the control and every flooding treated plant were significantly different, indicating that periodic flooding caused the delay of stem growth and decreased fruit number of all cultivars. The number of branches was influenced significantly by periodic flooding.In contrast, the plant survival rate showed no significant difference among all treatments. The higher the periodic flooding, the higher the risk of plant death and increased risk of production loss. Jaccard's clustering on RAPD profiling indicated that the group was developed based on cultivar more than periodic flooding. It was concluded that CH differed from others and had better endurance against periodic flooding, made it a right candidate for a breeding program.