A cross-sectional field study is reported in which a comprehensive model of work-home interference (WHI) was developed and tested among 166 medical residents of an academic hospital in the Netherlands. It was hypothesized that WHI functions as a critical mediating pathway in the relationship between work and home characteristics on the one hand, and work-related and general psychological health indicators on the other. The results revealed that one home characteristic and three work characteristics put pressure on the interface between the work and home life, that is, (1) having a spouse who works overtime frequently, (2) an unfavorable worktime schedule, (3) a high quantitative workload and (4) a problematic dependency on the superior. The results further showed that WHI was positively associated with emotional exhaustion and depersonalization (i.e. work-related health indicators), as well as with psychosomatic health complaints and sleep deprivation (i.e. general health indicators). More importantly, the results strongly supported our basic hypothesis that WHI mediates the impact of some work and home characteristics on psychological health indicators. This seems to be particularly true for the general health indicators: none of the home and work characteristics just mentioned, had a direct impact on these general indicators, independent of WHI. With respect to the work-related health indicators, particularly depersonalization, the mediating role of WHI was also strong, though less consistent. The theoretical and practical implications of the findings are discussed.