Chemical-looping combustion (CLC) is a promising technology for the combustion of gas or solid fuel with efficient use of energy and inherent separation of CO2. A reactivity study of CaSO4 oxygen carrier in CLC of methane was conducted in a laboratory scale fixed bed reactor. The oxygen carrier particles were exposed in six cycles of alternating reduction methane and oxidation air. A majority of CH4 reacted with CaSO4 to form CO2 and H2O. The oxidation was incomplete, possibly due to the CaSO4 product layer. The reactivity of CaSO4 oxygen carrier increased for the initial cycles but slightly decreased after four cycles. The product gas yields of CO2, CH4, and CO with cycles were analyzed. Carbon deposition during the reduction period was confirmed with the combustible gas (CO+H2) in the product gas and slight CO2 formed during the early stage of oxidation. The mechanism of carbon deposition and effect was also discussed. SO2 release behavior during reduction and oxidation was investigated, and the possible formation mechanism and mitigation method was discussed. The oxygen carrier conversion after the reduction decreased gradually in the cyclic test while it could not restore its oxygen capacity after the oxidation. The mass-based reaction rates during the reduction and oxidation also demonstrated the variation of reactivity of CaSO4 oxygen carrier. XRD analysis illustrated the phase change of CaSO4 oxygen carrier. CaS was the main reduction product, while a slight amount of CaO also formed in the cyclic test. ESEM analysis demonstrated the surface change of particles during the cyclic test. The reacted particles tested in the fixed bed reactor were not uniform in porosity. EDS analysis demonstrated the transfer of oxygen from CaSO4 to fuel gas while leaving CaS as the dominant reduced product. The results show that CaSO4 oxygen carrier may be an interesting candidate for oxygen carrier in CLC.