Background Research has yielded evidence for genetic and environmental factors influencing the risk of schizophrenia. Numerous environmental factors have been identified; however, the individual effects are small. The additive and interactive effects of multiple risk factors are not well elucidated. Twin pairs discordant for schizophrenia offer a unique opportunity to identify factors that differ between patients and unaffected co-twins, who are perfectly matched for age, sex and genetic background. Methods Register data were combined with clinical data for 216 twins including monozygotic (MZ) and dizygotic (DZ) proband pairs (one or both twins having a schizophrenia spectrum diagnosis) and MZ/DZ healthy control (HC) pairs. Logistic regression models were applied to predict (1) illness vulnerability (being a proband v. HC pair) and (2) illness status (being the patient v. unaffected co-twin). Risk factors included: A polygenic risk score (PRS) for schizophrenia, birth complications, birth weight, Apgar scores, paternal age, maternal smoking, season of birth, parental socioeconomic status, urbanicity, childhood trauma, estimated premorbid intelligence and cannabis. Results The PRS [odds ratio (OR) 1.6 (1.1-2.3)], childhood trauma [OR 4.5 (2.3-8.8)], and regular cannabis use [OR 8.3 (2.1-32.7)] independently predicted illness vulnerability as did an interaction between childhood trauma and cannabis use [OR 0.17 (0.03-0.9)]. Only regular cannabis use predicted having a schizophrenia spectrum diagnosis between patients and unaffected co-twins [OR 3.3 (1.1-10.4)]. Conclusion The findings suggest that several risk factors contribute to increasing schizophrenia spectrum vulnerability. Moreover, cannabis, a potentially completely avoidable environmental risk factor, seems to play a substantial role in schizophrenia pathology.