We investigate the positive relationships between high-performance work practices (HPWP) and employee health and well-being and examine the conflicting assumption that high work intensification arising from HPWP might offset these positive relationships. We present new insights on whether the combined use (or integrated effects) of HPWP has greater explanatory power on employee health, well-being, and work intensification compared to their isolated or independent effects. We use data from the 2004 British Workplace Employment Relations Survey (22,451 employees nested within 1,733 workplaces) and the 2010 British National Health Service Staff survey (164,916 employees nested within 386 workplaces). The results show that HPWP have positive combined effects in both contexts, and work intensification has a mediating role in some of the linkages investigated. The results also indicate that the combined use of HPWP may be sensitive to particular organizational settings, and may operate in some sectors but not in others.