The aim of this study was to investigate the effect of human blood exposure on the compressive strength of various calcium silicate-based cements. Two hundred and eighty-eight customised cylindrical moulds were randomly divided into three groups according to material used: ProRoot MTA, Biodentine or CEM cement (n = 96). Each group was divided into two subgroups according to exposure conditions: PBS or blood. Then, the compressive strength of the specimens was measured after 6 h, 24 h, 72 h and 7 days. The compressive strength of CEM cement could not be measured after 6 and 24 h regardless of the exposure conditions nor could the compressive strength of 6 h blood-exposed ProRoot MTA. The compressive strength of blood-exposed ProRoot MTA was only significantly lower after 6 h, but no difference was seen at other time intervals. Blood exposed did adversely affected the compressive strength of Biodentine. The compressive strength of all groups significantly increased over time (P < 0.005).