Salmonid rickettsial septicaemia (SRS) has caused significant losses in the Chilean salmonid aquaculture industry in the last two decades. While evidence suggests a strong association between sea lice burden and SRS severity, research to date has been conducted in tanks under controlled environmental conditions. Further, existing work does not account for the effect of the treatments used to control sea lice on SRS severity. This study measures the effect of lice burden, lice bathing treatments and the interaction between these two factors on SRS severity in salmonid aquaculture systems in Chile. Health and management data from nine commercial companies were combined with regulatory data to conduct a retrospective cage-level cohort study. Eight biologically plausible hypotheses were defined and investigated using an information-theoretic approach. The modelling approach was based on mixed-effect, negative binomial models of SRS-attributed mortality counts. A total of 6638 valid production cycles were included in the study, ranging from 01 January 2012 to 28 September 2018. A total of 35,864 cage-level observations were defined in two species: 28,529 in Atlantic salmon and 7335 in rainbow trout. Lice burden and rate of bath treatments were found individually to be risk factors for increased SRS-attributed mortality in both species. For Atlantic salmon, there was also a significant interaction between the levels of lice burden and rate of bath treatments so that increasing levels of one risk factor results in a dampening of the effect of the other factor. While these two factors were found to increase SRS mortality, much of the variability in mortality remained unexplained. Based on these findings, implications for lice management are discussed. The development of firm recommendations about optimal lice control programs should consider the findings of this study in conjunction with economic analysis. This study contributes to improved understanding of the complex epidemiology of SRS in the Chilean salmonid production system.