Red blood cell osmotic fragility (RBCOF) refers to susceptibility to hemolysis in vivo and in vitro. An increase in mean cellular hemoglobin concentration (MCHC) also reflects in vivo and in vitro hemolysis. Common inflammatory infectious diseases in dogs are often characterized by an increase in MCHC; however, it is not known if there is a concomitant increase in RBCOF. The objective of this study was to determine RBCOF in dogs with babesiosis, dirofilariosis, parvovirosis, pyometra, and canine distemper and to investigate whether RBCOF correlates with routine hematologic and biochemical parameters and lipoprotein fractions. The diagnosis of canine infectious disease was made and complete blood count, serum biochemical profiles, and lipoprotein electrophoresis were determined according to current institutional protocols. RBCOF of healthy control (n=8) and infected dogs (n=73) was measured with a phosphate-buffered saline dilution test, and mean corpuscular fragility (MCF) was calculated. MCF was increased in dirofilariosis, pyometra, and distemper; MCHC was increased in all infected groups; HDL was decreased in babesiosis, pyometra, and distemper compared with healthy controls. However, no correlation was found between these parameters. On the other hand, hematological and biochemical parameters, that are highly predictive of specific infections, correlated with MCF: ALP for babesiosis (r=0.415, P=0.035), urea (r=-0.488, P=0.034) for dirofilariosis, and leukocyte count (r=-0.820, P=0.046) for pyometra. Although elevated MCHC levels in all samples from infected dogs indicate hemolysis, RBCOF was elevated only in dirofilariosis, pyometra, and canine distemper, leading to the conclusion that these apparently related phenomena are controlled by different mechanisms.