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Introduction: Implementation of and compliance with smoke-free policies (SFPs) can be problematic in many low- and middle-income countries (LMICs) due to limited resources. This study evaluated knowledge, opinions and compliance related to Ghana's SFPs among owners and staff of hospitality venues by city, staff designation, and venue type., Methods: A cross-sectional study design was used in venue types including hotels, bars, pubs and restaurants in the three cities of Kumasi, Accra, and Tamale, in Ghana.Data were collected between July and September 2019. Interviewer administered face-to-face surveys were conducted with owners and staff (n=142) recruited from randomly selected hospitality venues (n=154) in these three large cities of Ghana. The relationship between knowledge, opinions, and compliance items on SFPs, and city, venue type and staff designation was first studied using χ 2 or a Fisher's exact test, and then with univariate logistic regression model analysis., Results: Of the 142 respondents, some had heard of Ghana's 2012 Tobacco Control Act (27.5%), smoking restriction in public places (29%), smoke-free places (22%), and display of 'no smoking' signage (6.3%). Knowledge levels were higher in Accra compared to Tamale (OR=3.08; 95% CI: 1.10-8.60). Staff designation and type of venue did not have any relationship with knowledge levels. Support for SFPs was over 80%, but opinions in support of SFPs were lower in Accra than Tamale (OR=0.25; 95% CI: 0.08-0.71). Compliance with SFPs was similar in the three cities. Hotels were three times more compliant compared to bars and pubs (OR=3.16; 95% CI: 1.48-6.71)., Conclusions: The study highlights the strong support for restriction of smoking in public places including hospitality venues despite poor knowledge and low compliance levels with the current SFPs. A review of the current SFP in Ghana together with education of hospitality staff on the benefits and requirements of SFPs is recommended., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2021 Singh A.)