Risk factors associated with work-related shoulder and neck myalgia were investigated in a case-control study with pairs matched for age, gender, and physical exposure. Guided interviews with standardized and self-constructed questionnaires were performed among manual (n = 15 pairs) and office (n = 24 pairs) workers. Perceived general tension was the variable with the strongest association with shoulder and neck pain in both work groups. Otherwise, the results in the two groups were very different, indicating that different risk factors and mechanisms were associated with shoulder and neck pain in the two work groups. The study provides background information for future attempts to establish causal relationships between physical and psychosocial exposure and shoulder and neck pain, which can be more accurately investigated in a longitudinal rather than a cross-sectional experimental design.