The COVID-19 pandemic and the measures implemented in the spring of 2020 to limit its spread may have had a significant impact on workers’ working conditions and health. The SAPRIS study, designed to understand the main epidemiological and social challenges of the COVID-19 pandemic, was launched by Inserm in April 2020 across four major generalist cohorts, including the Constances cohort. This cohort, which tracks more than 200,000 adults, provided an opportunity to assess this impact and to describe the health status of a population of salaried workers covered by the general social security system. The analysis presented focuses on respondents who were active at the time of the first Constances-SAPRIS questionnaire and describes the employment status and changes in working conditions of the target population, as well as changes in behavior and health status in terms of perceived general health, anxiety, and depression. These results were compared with those obtained from agricultural workers and the self-employed as part of the Coset program. The results show that nearly one in five employees under the general social security system ceased all professional activity in mid-April 2020, particularly office workers and manual laborers. Those who continued working were heavily affected by telework, primarily managers and intermediate-level professionals. The study’s findings paint a picture of a salaried population (under the general social security scheme) affected by the lockdown in terms of work stoppages or changes in working hours, but overall to a lesser extent than the non-agricultural self-employed population. An increase in alcohol consumption affected nearly one in four employees, particularly those who worked exclusively remotely. Regarding mental health, the main findings are that, among women, anxiety disorders were more common among those who continued to work in person, and that, among men, depressive disorders were more common among those who had ceased all work activity. The observations during this particular period reflect, overall, social isolation, a certain “exclusion” from the workplace, and changes in working conditions. It would be useful to document, over the longer term and outside the context of the pandemic, the impact on health and work organization of the new ways of working introduced during this period of crisis.