Background and Design: Because the current assessment of scleroderma through clinical skin scoring is subjective and imprecise, we devised fully quantitative measures of cutaneous involvement. First, we developed image analysis software for calculating the density of dermal collagen from 58 scleroderma and 327 control biopsy specimens. Second, using, a durometer gauge, we obtained measurements of skin hardness over 12 body regions for 13 patients with scleroderma and 100 controls. We obtained serial durometer measurements at 2-cm intenrals over the arms of four patients with scleroderma, correlating them with blinded assessments of skin score. Third, we produced two-dimensional laser Doppler maps of cutaneous blood flow over the dorsal aspect of the hands of 10 patients with scleroderma and 16 controls and, with software, we determined the mean red blood cell flux, density of arteriolar islands, and percentage of avascular area at each measured site. Results: Average collagen density was significantly higher in patients with scleroderma (88.5% +/- 6.9%) compared with that in controls (75% +/- 9.3%) (P<.001). Durometer measurements were significantly greater for patients with scleroderma (P<.05) over the finger, hand, wrist, forearm, and ventral aspect of the arm. In individual patients, the measurements paralleled with skin score. In patients with scleroderma, mean red blood cell flux (483.2 +/- 421.2 mV) and arteriolar island density (1.4 +/- 0.5/cm(2)) were significantly greater than were the control averages (276.3 +/- 146.3 mV [P<.03] and 1.0 +/- 0.5/cm(2) [P<.013], respectively). Conclusions: Dermal collagen density and durometer measurements of skin hardness accurately quantify skin sclerosis in scleroderma and permit the determination of sclerotic borders, respectively. Increased cutaneous red blood cell flux and greater use of microvascular reserve reflect defects in vascular regulation inherent to the disease. These reproducible measurements will allow us to more precisely monitor the progression of scleroderma, evaluate its response to experimental treatments, and investigate its pathogenetic origins.