Healthcare workers face difficult working conditions, particularly where HIV and tuberculosis add to understaffing. Questionnaires, workplace assessments, and discussion groups were conducted at a regional hospital in South Africa to obtain baseline data and input from the workforce in designing interventions. Findings highlighted weaknesses in knowledge, for example regarding the use of N95 respirators and safe handling of sharps, and suggested the need for improved training. Access to supplies and personal protective equipment was the major reported reason for failure to follow proper procedures; this was confirmed by workplace assessments. Discussion groups highlighted the important role for worker Health and Safety Committees (HSC), including in combating stigma and encouraging reporting. Interest in data to support decision-making resulted in development of the Occupational Health and Safety Information System (OHASIS); further training of HSCs is still needed. Multi-stakeholder international collaboration aimed at building HSC capacity is well-received.