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This paper presents a theoretical study of fifth-harmonic generation (FHG) in an isotropic media. Two schemes are discussed-cascade generation in which the fifth harmonic results from successive nonlinear interactions in two separate elements, and direct generation where the fifth harmonic is produced in an isotropic media with third-and fifth-order nonlinear susceptibilities. In the plane-wave approximation almost full conversion of the pumping energy into the fifth harmonic is found to be possible. FHG with a focused Gaussian beam is also investigated. To determine the optimum conditions for FHG in the cascade scheme, the theory of four-wave mixing of light beams with arbitrary confocal parameters and waist locations is developed. In media with third- and fifth-order nonlinearity, the fifth harmonic results from step and direct processes. The interference between these two processes is discussed. Numerical calculations are presented for metal vapor-gas mixtures and Nd:glass laser pumping radiation.