In a 26-year-old white male with Buerger's disease we hypothesized that gene polymorphisms which confer susceptibility to arterial spasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C MTHFR compound heterozygosity with decreased bioavailability of nitric oxide (NO) interacted with cigarette-cannabis smoking, as gene-environment interactive etiologies for the peripheral artery spasm, thrombosis, and arterial occlusion of Buerger's disease. In a 26-year-old male who had heavily smoked cigarettes-cannabis, Buerger's disease with rapid progression of bilateral lower limb gangrenous ischemia and intractable ischemic pain on rest despite smoking cessation threatened high above-knee amputations. There was complete arterial occlusion at the level of the left popliteal trifurcation. After documentation of thrombophilic C677T-A1298C compound MTHFR heterozygosity, folic acid 5 mg, vitamin B6 100 mg, and vitamin B12 2000 μg/day were started to optimize homocysteine metabolism and to reduce asymmetric dimethylarginine (ADMA) levels, an endogenous inhibitor of NO synthase. L-Arginine (15 g/day) was given as an approach to increase vasodilatory NO production via endothelial NO synthase (eNOS). Within 8 weeks on therapy, gangrenous ulcers on the right foot and leg healed, pain subsided, and peripheral arterial pulses normalized. Previously existing gangrene of the left great toe and second toe became complicated with cellulitis, necessitating below knee amputation. Healing was subsequently uneventful with bilateral normal peripheral arterial pulses. PCR analyses revealed heterozygosity for stromelysin-1 5A/6A and eNOS T-786C polymorphisms, previously shown to confer susceptibility to coronary artery spasm and myocardial infarction in synergy with cigarette smoking. In cigarette-cannabis smokers, we speculate that the development and severity of Buerger's disease are related to a gene-environment interaction in subjects heterozygous for the stromelysin-1 5A/6A and eNOS T-786C polymorphisms, as well as C677T-A1298C MTHFR compound heterozygosity, which altogether reduce endogenous NO-mediated vasodilatation. In such cases, Buerger's disease can successfully be treated by increasing NO production by giving oral L-arginine (15 g/day) while also optimizing homocysteine metabolism by provision of folic acid (5 mg), vitamin B6 (100 mg), and vitamin B12 (2000 μg)/day.