Introduction. Recent evidence suggests that blocking inducible nitric oxide (NO) synthase in the penis may exacerbate fibrotic processes and that application of medications known to increase NO in tissues may prevent fibrosis. Aim. To report the use of an antifibrotic regimen consisting of medications known to upregulate NO production in two patients with refractory priapism. Methods. Two patients presented with priapism of greater than 48-hour duration. After corporal aspiration/irrigation and shunting procedures failed, both were prescribed a daily antifibrotic regimen comprising the phosphodiesterase inhibitors pentoxifylline and sildenafil, and the NO precursor, L-arginine. Results. At 1 year, both patients were found to have supple corpora without evidence of corporal fibrosis. Conclusions. An antifibrotic regimen consisting of upregulators of NO production may ameliorate the corporal fibrosis associated with recalcitrant priapism.