Psychosocial safety climate (PSC) refers to a specific organizational climate for the psychological health of workers. It is largely determined by management and at low levels is proposed as a latent pathogen for psychosocial risk factors and psychological strain. Using an extended Job Demands-Control-Support framework, we predicted the (24 month) cross-level effects of PSC on psychological strain via work conditions. We used a novel design whereby data from two unrelated samples of nurses working in remote areas were used across time (N=202, Time 1; N=163, Time 2), matched at the work unit level (N= 48). Using hierarchical linear modelling we found that unit PSC assessed by nurses predicted work conditions (workload, control, supervisor support) and psychological strain in different nurses in the same work unit 24 months later. There was evidence that the between-group relationship between unit PSC and psychological strain was mediated via Time 2 work conditions (workload, job control) as well as Time 1 emotional demands. The results support a multilevel work stress model with PSC as a plausible primary cause, or “cause of the causes”, of work-related strain. The study adds to the literature that identifies organizational contextual factors as origins of the work stress process.