Abstract Background Paracetamol is widely used to treat postoperative pain and is well known for its morphine-sparing effect. Therefore, the effect of morphine–paracetamol combination can be synergistic, additive, or infra-additive. The primary aim of our study is to define the median effective analgesic doses (ED50s) of paracetamol, morphine, and the combination of both. Also, the nature of the interaction for postoperative pain after moderately painful surgery using an up-and-down method and isobolographic analysis was determined. Methods Ninety patients, undergoing moderately painful surgery, were included in one of the three groups. Determination of the median ED50s was performed by the Dixon and Mood up-and-down method. Initial doses were 1.5 g and 5 mg, with dose adjustment intervals of 0.5 g and 1 mg, in the paracetamol and morphine groups, respectively. The initial doses of paracetamol and morphine were 1.5 g and 3 mg, in the paracetamol–morphine combination group with dose adjustment intervals of 0.25 g for paracetamol and 0.5 mg for morphine. Analgesic efficacy was defined as a reduction to or Results The median ED50s of paracetamol and morphine were 2.1 g and 5 mg, respectively. The median ED50 of the combination was 1.3 g for paracetamol and 2.7 mg for morphine. Conclusions Our study showed that the combination of the paracetamol and morphine produces an additive analgesic effect. Clinical trial registration NCT01366313.