Background: The impact of burns and colds on human skin microcirculation and histomorphology has not been compared as yet. Reflectance confocal microscopy (RCM) enables in vivo insight in human skin on cellular and subcellular levels. We evaluated analogies and differences of thermal injuries on microcirculation and histomorphology in vivo using RCM. Methods: Local superficial burn (6 female, 4 male; aged 28.4 ± 2.9 years, burn group) versus superficial cold (4 female, 6 male; aged 30.4 ± 5.2 years, cold group) was induced on the dorsum of the hand in an experimental immersion hand model. In vivo RCM was performed prior (control), immediately (t1) and 15 minutes (t2) following thermal injury to evaluate: Individual blood cell flow (IBCF), functional capillary density (FCD), epidermal thickness (ET), and granular cell size (GCS). Results: In the burn group, IBCF was increased at t1 (78.02 ± 2.60/min) and remained elevated at t2 (84.16 ± 3.04/min). In the cold group, IBCF decreased at t1 (12.62 ± 2.12 min) and increased at t2 (74.24 ± 3.14/min, P < 0.05) compared to the controls (58.23 ± 3.21/min). FCD was 6.74 ± 0.52/mm2 in controls and increased at both t1 (7.82 ± 0.72/mm2) and t2 (8.02 ± 0.81/mm2) in the burn group. In the cold group, FCD decreased at t1 (2.60 ± 0.42/mm2) and increased at t2 (7.92 ± 0.44/mm2, P < 0.05). ET increased at both t1 (43.12 ± 4.08 μm, P > 0.05) and t2 (47.26 ± 4.72 μm, P < 0.05) in the burn group. In the cold group, ET decreased at t1 (39.92 ± 3.14 μm, P > 0.05) and increased at t2 (44.72 ± 4.06 μm, P < 0.05) compared to the controls (41.26 ± 3.82 μm). Control GCS was 726.9 ± 59.4 μm2 and increased at both t1 (739.8 ± 69.8 μm2, P > 0.05) and t2 (762.6 ± 71.4 μm2, P < 0.05) in the burn group. In the cold group, GCS decreased at t1 (712.4 ± 53.8 μm2, P > 0.05) and increased at t2 (742.6 ± 64.8 μm2, P < 0.05). Conclusions: Superficial burn induces more cellular destruction and cold leads to huge fluctuation in tissue perfusion, however, with moderate impact on histomorphology. The effect on dermal capillaries suggests a selective neural control and cold injuries might down-regulate this system, much more than burns can activate it. Microsc. Res. Tech., 2011. © 2011 Wiley-Liss, Inc.