Importance: The risk of cancer developing in people with psoriasis has raised some concern, with little clarity regarding differentiation in risk according to psoriasis severity. Objective: To conduct a systematic review and meta-analysis of observational studies on the risk of cancer incidence and mortality in people with psoriasis. Data Sources: Six electronic databases (MEDLINE, Embase, MEDLINE in Process, Cochrane Central Register, Web of Science, and LILACS [Literatura Latino-Americana e do Caribe em Ciências da Saúde]) were searched from inception to November 15, 2017, for eligible studies. Study Selection: Cohort and case-control studies that provided estimates of the risk of cancer incidence or cancer mortality associated with psoriasis were included. Data Extraction and Synthesis: Data were extracted relating to study design, study population, and risk estimates. Study-specific estimates of the relative risk (RR) were combined using a random-effects model. Heterogeneity was quantified using the I2 statistic. Data were analyzed from April 9, 2018, through February 22, 2019. Main Outcomes and Measures: Pooled RR estimates for cancer incidence and cancer mortality for psoriasis cohorts compared with people without psoriasis. Results: A total of 58 unique studies were included, with quality varying for the incidence and the mortality studies. Severe psoriasis (RR, 1.22; 95% CI, 1.08-1.39 [9 studies]) and all severities of psoriasis (RR, 1.18; 95% CI, 1.06-1.31 [7 studies]) were associated with an increased risk of cancer (overall), and associations were found for a range of site-specific cancers, including colon (RR, 1.18 [95% CI, 1.03-1.35]), colorectal (RR, 1.34 [95% CI, 1.06-1.70]), kidney (RR, 1.58 [95% CI, 1.11-2.24]), laryngeal (RR, 1.79 [95% CI, 1.06-3.01]), liver (RR, 1.83 [95% CI, 1.28-2.61]), lymphoma (RR, 1.40 [95% CI, 1.24-1.57]), non-Hodgkin lymphoma (RR, 1.28 [95% CI, 1.15-1.43]), keratinocyte cancers (RR, 1.71 [95% CI, 1.08-2.71]), esophageal (RR, 2.05 [95% CI, 1.04-4.07]), oral cavity (RR, 2.80 [95% CI, 1.99-3.93]), and pancreatic (RR, 1.41 [95% CI, 1.16-1.73]). Overall cancer mortality risk was higher in patients with severe psoriasis (RR, 1.22; 95% CI, 1.08-1.38 [4 studies]). Specifically, liver (RR, 1.43 [95% CI, 1.09-1.88]), esophageal (RR, 2.53 [95% CI, 1.87-3.41]), and pancreatic (RR, 1.31 [95% CI, 1.02-1.69]) cancer mortality were found to be elevated in those with severe psoriasis. The heterogeneity of estimates was often very high despite stratification. Marked attenuation of risk was found in those studies that adjusted estimates for smoking, alcohol consumption, and obesity. Conclusions and Relevance: In this study, people with psoriasis appeared to have an increased risk of cancer incidence and cancer-related mortality involving a range of site-specific cancers. Future research examining specific lifestyle factors, treatments, and the inflammatory processes that contribute to psoriasis may help provide additional information on the underlying mechanisms for the apparent increased cancer risk.