The study developed an analytical procedure for determination of Zn in human blood was developed taking into account spectral and chemical interferences. The ICP’s operational settings including radio frequency power, the plasma, and nebulizer gas flow rates, and the sample introduction rate as well as the digestion conditions were established using response surface methodology (RSM). The paper also analyzes the usefulness of two wet decomposition methods – the closed system with microwave heating in Teflon bombs and the semi-closed system with heating in a heating block. The best ICP operating conditions were as follows: plasma, and nebulizer gas flow rates: 14 and 0.5 L min^-1 respectively, radio frequency power 1400 W, and sample introduction rate 1.5 mL min^-1. Three analytical lines most commonly used in the quantitative analysis of Zn by the ICP-OES technique were also tested for their applicability to biological material (whole human blood). Our results showed that the Zn signal overlapped with the Fe signal at 213.856 nm, and this line should be avoided in Zn analysis in samples with high content of Fe. There was also a significant effect of chemical interference from the digested sample matrix. The elaborated methodology was validated based on certified material and verified using real blood samples. Calibration with most abundant elements matrix provided high-accuracy determination.