In hopes of increasing etiologic specificity of non-Hodgkin lymphoma (NHL), we defined NHL tumors by acquired chromosomal translocations involving the immunoglobulin heavy chain (any IGH), t(14;18), t(8;14) and BCL6 translocations using fluorescence in situ hybridization (FISH) assays of archival paraffin-embedded tumor blocks. Translocations were identified in samples from over 200 unselected NHL cases originally enrolled in the National Cancer Institute's Factors Affecting Rural Men (FARM) study (1981-1984). We re-evaluated reported associations between tobacco exposures and t(14;18)-NHL case-subtypes that were previously defined based on polymerase chain reaction (PCR) assays. We also evaluated bcl-2 protein expression based on immunohistochemistry. t(14;18)-FISH case-subtypes were compared with t(14;18)-PCR case-subtypes by frequency according to histologic subtype and bcl-2 status. Case:control associations were estimated using multivariate polytomous logistic regression for t(14;18)-NHL and factors including tobacco use, family history of hemolymphatic cancer, and hair dye use. The expectation-maximization (EM) algorithm was applied to case:control models to reduce bias due to missing case-subtype data. BCL6 translocations, t(8;14), and other IGH translocations were uncommon in the study population. t(14;18) was identified in 53% of cases, including 39% of diffuse large cell lymphomas (26 of 66 cases) and 81% of follicular lymphomas (35 of 43 cases). FISH assays detected almost twice as many t(14;18)-positive follicular lymphomas as PCR assays (44%) run on the same samples. The majority of cases expressed bcl-2, including 87% of t(14;18)-positive cases and 58% of t(14;18)-negative cases. Adjusting for age, state, and proxy status, t(14;18)-negative NHL was associated with any tobacco use (OR=1.98, 95% CI=1.09-3.59) and cigarette smoking, without evidence of a linear dose-response with increasing pack-years or intensity of smoking. In contrast, tobacco and cigarette use were not clearly associated with t(14;18)-positive NHL or with bcl-2 case-subtypes. Our results support the use of FISH assays of archival samples to identify t(14;18)-NHL case-subtypes. The association between t(14;18)-negative NHL and cigarette smoking was unexpected given previous evidence of associations between smoking and follicular lymphoma (which is largely t(14;18)-positive). Additional molecular characterization of t(14;18)-negative cases may clarify whether the association between tobacco use and t(14;18)-negative NHL was causal versus an artifact of chance or bias.