Worldwide, legislative and governmental efforts are focusing on establishing simple screening tools for identifying those chemicals most likely to cause adverse effects without experimentally testing all chemicals of regulatory concern. This is because even the most basic biological testing of compounds of concern, apart from requiring a huge number of test animals, would be neither resource nor time effective. Thus, alternative approaches such as the one proposed here, quantitative structure-activity relationship (QSAR) modelling, are increasingly being used for identifying the potential health hazards and subsequent regulation of new industrial chemicals. This paper follows up on our earlier work that demonstrated the use of the TOPological Substructural MOlecular DEsign (TOPS-MODE) approach to QSAR modelling for predictions of the carcinogenic potency of nitroso compounds. The data set comprises 56 nitroso compounds which have been bio-assayed in female rats and administered by the oral water route. The QSAR model was able to account for about 81% of the variance in the experimental activity and exhibited good cross-validation statistics. A reasonable interpretation of the TOPS-MODE descriptors was achieved by means of bond contributions, which in turn afforded the recognition of structural alerts (SAs) regarding carcinogenicity. A comparison of the SAs obtained from different data sets showed that experimental factors, such as the sex and the oral administration route, exert a major influence on the carcinogenicity of nitroso compounds. The present and previous QSAR models combined together provide a reliable tool for estimating the carcinogenic potency of yet untested nitroso compounds and they should allow the identification of SAs, which can be used as the basis of prediction systems for the rodent carcinogenicity of these compounds.