Background: Studies showed the impact of sex and onset site (spinal or bulbar) on disease onset and survival in ALS. However, they mainly result from cross-sectional or survival analysis, and the interaction of sex and onset site on the different proxies of disease trajectory has not been fully investigated. Methods: We selected all patients with repeated observations in the PRO-ACT database. We divided them into four groups depending on their sex and onset site. We estimated a multivariate disease progression model, named ALS Course Map, to investigate the combined temporal changes of the four sub-scores of the revised ALS Functional Rating Scale (ALSFRSr), the forced vital capacity (FVC), and the body mass index (BMI). We then compared the progression rate, the estimated age at onset, and the relative progression of the outcomes across each group. Results: We included 1,438 patients from the PRO-ACT database. They were 51% men with spinal onset, 12% men with bulbar onset, 26% women with spinal onset, and 11% women with bulbar onset. We showed a significant influence of both sex and onset site on the ALSFRSr progression. The BMI decreased 8.9 months earlier (95% CI = [3.9, 13.8]) in women than men, after correction for the onset site. Among patients with bulbar onset, FVC was impaired 2.6 months earlier (95% CI = [0.6, 4.6]) in women. Conclusion: Using a multivariable disease modelling approach, we showed that sex and onset site are important drivers of the progression of motor function, BMI, and FVC decline.