Background: Nontraumatic complaints of arm, neck, and shoulder (CANS) represent an important health issue, with a high prevalence in the general working age population and huge economic impact. Nevertheless, only few prospective cohort studies for the outcome of CANS are available. Objectives: The purpose of this study was to identify disability trajectories and associated prognostic factors during a 2-year follow-up of patients with a new episode of CANS in primary care. Design: This was a prospective cohort study. Methods: Data of 682 participants were collected through questionnaires at baseline and every 6 months thereafter. Disability was measured with the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH). Latent class growth mixture (LCGM) modeling was used to identify clinically meaningful groups of patients who were similar in their disability trajectory during follow-up. Multivariate multinomial regression analysis was used to evaluate associations between sociodemographic, complaint-related, physical, and psychosocial variables and the identified disability trajectories. Results: Three disability trajectories were identified: fast recovery (67.6%), modest recovery (23.6%), and continuous high disability (8.8%). A high level of somatization was the most important baseline predictor of continuous high disability. Furthermore, poor general health, widespread complaints, and medium level of somatization were associated with this trajectory and >3 months complaint duration, musculoskeletal comorbidity, female sex, history of trauma, low educational level, low social support, and high complaint severity were associated with both continuous high disability and modest recovery. Age, kinesiophobia, and catastrophizing showed significant associations only with modest recovery. Limitations: Loss to follow-up ranged from 10% to 22% at each follow-up measurement. Disabilities were assessed only with the DASH and not with physical tests: Misclassification by general practitioners regarding specific or nonspecific diagnostic category might have occurred. The decision for optimal LCGM model, resulting in the disability trajectories, remains arbitrary to some extent. Conclusions: Three trajectories described the course of disabilities due to CANS. Several prognostic indicators were identified that can easily be recognized in primary care. As some of these prognostic indicators may be amenable for change, their presence in the early stages of CANS may lead to more intensive or additional interventions (eg, psychological or multidisciplinary therapy). Further research focusing on the use of these prognostic indicators in treatment decisions is needed to further substantiate their predictive value.