OBJECTIVES: Previous smaller case series suggested that cannabis smoking may cause spontaneous pneumothorax, but this finding remains controversial. We investigated the possible association between smoking tobacco and cannabis and the risk of having a primary spontaneous pneumothorax in a large, homogeneous cohort of young, healthy individuals. METHODS: In a case-control study, we prospectively investigated young (≤40 years) patients admitted in Western Denmark from 2009 to 2016 with their first episode of primary spontaneous pneumothorax. Baseline characteristics and smoking habits including both tobacco and cannabis were obtained from questionnaires presented on admittance. We compared our findings with those of a population-based control group matched by age, sex and geographical area. Calculated odds ratios were compared using the Fisher's exact test for small frequencies and the χ 2 test or the Mann-Whitney test for larger frequencies. RESULTS: A total of 416 patients participated (male/female ratio = 3.9). We observed a significantly increased risk of primary spontaneous pneumothorax in daily smokers compared with female never smokers (odds ratio = 8.10, 95% confidence interval: 4.61-14.14, P < 0.001) and male never smokers (odds ratio = 4.85, 95% confidence interval: 3.23-7.19, P < 0.001). The combination of smoking both cannabis and tobacco in men increased the risk of spontaneous pneumothorax significantly (odds ratio = 8.74, 95% confidence interval: 4.30-19.51, P < 0.001). In contrast, the cannabis habits of female patients did not differ from those of the Danish population in general. CONCLUSIONS: Combined smoking of tobacco and cannabis significantly aggravates the risk of having a primary spontaneous pneumothorax in young men compared to both never smokers and daily smokers.