Background: Hyperhomocysteinemia is an independent risk factor for atherothrombotic disease and venous thrombosis. The effects of hyperhomocysteinemia on the microcirculation were studied in vascular diseases. The authors aimed to investigate the effects of hyperhomocysteinemia on the microcirculation of random-pattern skin flaps. Methods: Twenty-two male Sprague-Dawley rats, divided into two groups, were used in this study. The rats in group 1 (control) were fed the TD.07112 diet, and the rats in group 2 (experimental group) were fed the TD.07114 diet, enriched in methionine for 30 days, to induce severe hyperhomocysteinemia. The plasma homocysteine, folic acid, vitamin B12, and vitamin B6 levels were evaluated on days 0 and 30. Distally based skin flaps were elevated on day 30 and evaluated by direct observation, microangiography, and light microscopy on day 37. Results: Mean homocysteine blood levels were 211.76 ± 56.55 μM/liter in group 2 and 14.48 ± 2.00 μM/liter in group 1 on day 30. The rate of necrosis was significantly higher in group 2 (59.00 ± 4.38 percent) compared with group 1 (32.54 ± 6.13 percent; p < 0.01). Microangiographic findings were similar to direct observation results. Microvessel calibration was reduced in group 2. In group 1, structures of epidermis and dermis were normal; however, there was a slight mononuclear cell infiltration along with thick collagen fibers. A more prominent mononuclear cell infiltration with fields of loose epidermis, associated with inflammation and infiltration, were observed in group 2. Conclusion: The authors demonstrated, for the first time, that hyperhomocysteinemia severely suppressed the microvasculature of skin flaps, as shown by increased flap necrosis and reduced microvessel calibration in the experimental group. © 2011 by the American Society of Plastic Surgeons.