Objectives: To evaluate the effectiveness of safety guidelines in the workplace, the authors analyzed the work-related exposure to SARS-CoV-2 and the source of COVID‑19 infections among healthcare workers (HCWs), together with the use of personal protective equipment (PPE). Material and Methods: A cross-sectional prospective study was conducted in tertiary hospitals in the Uusimaa region, Finland, with 1072 volunteers being enrolled in the study from among the HCWs at the Helsinki University Hospital. Overall, 866 (80.8%) HCWs (including 588 nurses, 170 doctors, and 108 laboratory and medical imaging nurses) completed the questionnaire by July 15, 2020, with 52% of the participants taking care of COVID‑19 patients. The participants answered a structured questionnaire regarding their use of PPE, the ability to follow safety guidelines, exposure to COVID‑19, and the source of potential COVID‑19 infections. The participants with COVID‑19 symptoms were tested with the SARS-CoV-2 realtime polymerase chain reaction method. All infected participants were contacted, and their answers were confirmed regarding COVID‑19 exposure. Results: In total, 41 (4.7%) participants tested positive for SARS-CoV-2, with 22 (53.6%) of infections being confirmed or likely occupational, and 12 (29.3%) originating from colleagues. In 14 cases (63.6%), occupational infections occurred while using a surgical mask, and all infections originating from patients occurred while using a surgical mask or no mask at all. No occupational infections were found while using an FFP2/3 respirator and following aerosol precautions. The combined odds ratio for working at an intensive care unit, an emergency department, or a ward was 3.4 (95% CI: 1.2–9.2, p = 0.016). Conclusions: A high infection rate was found among HCWs despite safety guidelines. Based on these findings, the authors recommend the use of FFP2/3 respirators in all patient contacts with confirmed or suspected COVID‑19, along with the use of universal masking, also in personnel rooms. Int J Occup Med Environ Health. 2021;34(2):239–49