Smear-positive pulmonary tuberculosis (PTB) is more infectious compared to smear-negative PTB and have great significance for epidemiology and infection control. The prevalence of smear-positive PTB rarely affects males and females equally. Hence, we aimed to identify the sex-related differences in the prevalence of smear-positive PTB and its associated factors in Kuala Lumpur, Malaysia. A cross-sectional study was conducted using data from the National Tuberculosis Information System (TBIS) from 1 January, 2015, to 31 December, 2019. The study population was selected using simple random sampling from the list of registered PTB patients in TBIS. The criteria for inclusion were all Malaysian adults aged [greater than or equal to]18 years residing in Kuala Lumpur and registered as PTB in TBIS. Factors associated with smear-positive PTB in male and female patients were determined using multiple logistic regression analysis. Overall prevalence of smear-positive PTB was 68.6%, and male patients predominated (71%). The male:female prevalence ratio of smear-positive PTB was 2.4:1. Male patients who worked as machine operators and elementary workers (adjusted odds ratio (aOR) 2.23, 95% confidence interval (CI) 1.24-4.02, p = 0.007), were self-employed (aOR 2.58, 95% CI 1.46-4.56, p = 0.001), lived in a residence categorized as 'other' (aOR 2.49, 95% CI 1.28-4.86, p = 0.007) and were smokers (aOR 1.37, 95% CI 1.01-1.87, p = 0.045) had higher odds for smear-positive PTB. Meanwhile, female patients with diabetes mellitus had higher odds for smear-positive PTB (aOR 1.92, 95% CI 1.05-3.54, p = 0.035), while female patients who were healthcare workers had lower odds (aOR 0.33, 95% CI 0.12, 0.94, p = 0.039). The prevalence of smear-positive PTB is higher in males compared to females. The factors associated with smear-positive PTB differed based on sex. The current TB control program, especially on smear-positive PTB, should likely be strategized and stratified by sex.