The acute phase reaction is a molecular response to noxious stimuli. Over 50 glycoproteins have been identified as reactants. While this is likely a protective response, some of the changes could be detrimental to body homeostasis. The objective of this study was to examine whether an acute phase reaction occurs in diabetic patients with foot ulcers. In age- and sex-matched populations, measurements of C-reactive protein, fibrinogen, albumin, hematocrit, whole blood viscosity and protein C were performed on: (i) 24 diabetic patients with a foot ulcer (group A); (ii) eight diabetic patients without foot ulcer (group B); and (iii) seven patients without diabetes (group C). Analysis of variance was used to compare means of each respective group (mean (s.d.)). Group A demonstrated an increase in C-reactive protein (5.6 (5.4) mg/dl) compared with group B (0.78 (0.46) mg/dl; P = 0.013) and group C (0.71 (0.26) mg/dl; P = 0.026). Fibrinogen was also increased in group A (619 (205) mg/dl) compared with group B (310 (58) mg/dl; P = 0.005) and group C (370 (88) mg/dl; P = 0.04). Hematocrit (37 (6)%) and albumin (3.5 (0.5) g/dl) were decreased in group A compared with group B (hematocrit 46 (4)%; P < 0.0001; albumin 4.3 (0.3) g/dl; P = 0.0005) and group C (hematocrit 45 (3)%; P = 0.005; albumin 4.6 (0.3) g/dl; P < 0.0001). No difference was found in whole blood viscosity and levels of protein C. There also was no significant difference demonstrated between any of the parameters studied when comparing groups B and C. In conclusion, these results indicate that diabetic patients with a foot ulcer undergo an acute phase reaction as evidenced by a rise in C-reactive protein and fibrinogen compared with diabetic patients without a foot ulcer and normal control patients. As more is learned about the acute phase reaction, this information may prove valuable in the management of the diabetic patient.