Antibiotic computerised decision support systems (CDSSs) were developed to facilitate optimal prescribing, but acceptance of their recommendations has remained low. We aimed to evaluate physicians' perceptions and attitudes toward antibiotic CDSSs and determine psychosocial factors associated with acceptance of CDSS recommendations for empirical therapy. A mixed methods study was conducted in an adult tertiary-care hospital in Singapore, with its in-house antibiotic CDSS that integrates antimicrobial stewardship with electronic prescribing. Focus group discussions were conducted among purposively sampled physicians and data were analysed using the framework approach. Emerging themes were included in the questionnaire with newly developed scales for the subsequent cross-sectional survey involving all physicians. Principal components analysis was performed to derive the latent factor structure that was later applied in multivariate analyses. Physicians expressed confidence in the credibility of CDSS recommendations. Junior physicians accepted CDSS recommendations most of the time, whilst senior physicians acknowledged overriding recommendations in complex patients with multiple infections or allergies. Willingness to consult the CDSS for common and complex infections (OR=1.68, 95% CI 1.16-2.44) and preference for personal or team decision (OR=0.61, 95% CI 0.43-0.85) were associated with acceptance of CDSS recommendations. Cronbach's α for scales measuring physicians' attitudes and perceptions towards acceptance of CDSS recommendations ranged from 0.64 to 0.88. Physicians' willingness to consult an antibiotic CDSS determined acceptance of its recommendations. Physicians would choose to exercise their own or clinical team's decision over CDSS recommendations in complex patient situations when the antibiotic prescribing needs were not met.