The stress relaxation (SR) process in zirconium-based alloys is intimately related to creep behavior as stress is diminished with time by creep. Open literature data show a complex and not fully understood relation between the primary and quasi-steady-state creep rates and the corresponding SR rates; in particular, it was observed that higher primary SR rates occur under irradiation. To further investigate this topic, in-reactor SR experiments were conducted on pre-irradiated zirconium alloy specimens. A unique four-point bend (4PB) technique was applied to measure SR of pre-irradiated and unirradiated rectangular specimens (35 by 6.5 by 0.8 mm in size) at regular intervals during their irradiation in the RBT-6 research reactor and a sibling out-reactor rig. The 4PB method had never been applied previously to highly pre-irradiated (up to 34 dpa) and prehydrided (up to 339 ppm) small specimens of zirconium alloys. The measured SR behavior can be analyzed with various creep behavior models. In addition, the alloy variants tested in this study were also a subset of those from a previous study on irradiation growth behavior. The unique loading fixture utilized can simultaneously apply 4PB loads on up to six specimens, without need for removing the specimens from the fixture to record SR versus time data. Additional fast fluence accrued during SR testing in RBT-6 was minimal. Post-test examinations on selected specimens were performed by metallography and transmission electron microscopy. This paper describes (i) the design of the loading fixture, (ii) in-reactor and out-reactor SR data, (iii) the SR data trends, especially the lack of any significant dependence of SR with c-component loop density and hydrogen, (iv) some observations on the effects of alloying additions on SR, (v) application of a simple phenomenological creep model to the SR data, and (vi) the post-test characterizations of SR test samples.