BACKGROUND: We evaluate the impact of radiation and its early versus late effects on internal mammary vessel histomorphometry and implications for autologous breast reconstruction. METHODS: Patients received no radiation or radiation within the previous 6 weeks (early) or at least 6 months prior to biopsy (late) of the internal mammary vessels during free flap surgery. Clinical outcomes, and vessel measurements and markers for macrophages, smooth muscle actin (SM-ACTIN), elastin, and collagen were analyzed. RESULTS: We analyzed 36 internal mammary arteries (IMAs) and veins (IMV) in 22 patients. Six had no radiation, 12 had radiation less than 6 weeks, and 18 had radiation more than 6 months ago. Demographics, surgical variables, and cardiovascular comorbidity did not differ between groups. Macrophage counts were higher in patients who had radiation (p < 0.001) and in the early group when compared with the late group (p = 0.03). There were similar findings in the IMV. Intimal thickness of the IMA increased significantly after radiation (p < 0.001), particularly in the late group when compared with the early group (p = 0.007). Intima-media thickness of the IMV was significantly elevated (p = 0.02) after radiotherapy. Radiation decreased percentage of SM-ACTIN in the IMA (p = 0.05). Other histomorphometric parameters did not differ significantly. CONCLUSION: Higher macrophage counts but less intimal thickening of the IMA differentiates donor vessels utilized within 6 weeks of radiotherapy and those performed after 6 months or more. Although the timing of reconstruction is based on several other factors, histologic parameters support reconstruction within 6 weeks of radiation therapy.