Tripartite motif (TRIM) family proteins play important regulatory roles in innate immune responses, the dysregulation of which cause several infectious diseases. However, the role and function of TRIM family proteins during tuberculosis (TB) infection remains unclear. In this study, we employed real-time quantitative PCR to profile the transcript levels of 72 TRIM genes from a cohort of 5 active TB patients, 5 latent tuberculosis infection (LTBI) subjects, and 5 healthy controls (HCs) in an initial discovery phase. The notable TRIM genes were assessed by in vitro cell infection experiments and further validated in another independent cohort (36 active TB, 24 LTBI and 28 HCs). The receiver operating characteristic (ROC) was used to analyze the diagnostic power of these TRIM genes. Our results revealed that 20 TRIM genes were decreased in active TB compared to LTBI and HCs. In addition, TRIM4, 16, 27, 32, 35, 46, 47, 65 and 68 were further shown to be downregulated in Mycobacterium smegmatis-infected macrophages and were found to be closely correlated with infection time and initial bacteria loads. Furthermore, the ROC analyses showed that TRIM4, 27 and 65 all exhibited the highest areas under the curve (AUC) values of 1.00 in discriminating active TB from LTBI and HCs. Moreover, TRIM27 combined with TRIM32 for an improved AUC value of 0.81 in discriminating LTBI from HCs. These results suggest that TRIM gene dysregulation might be involved in the pathogenesis of TB and that these genes could serve as potential biomarkers for indicating TB status.