Background: There have been reports of a high frequency of metachronous cancers in patients diagnosed with GIST. The purpose of this study was to identify and describe patients with GIST who develop second primary cancers, and to calculate standardized incidence ratios (SIRs) to quantify the risk of additional malignancy. Methods: This was a retrospective, population-based cohort study using SEER data. Individuals diagnosed with GIST from 2001-2009 were identified as having a malignant primary tumor in the digestive tract, and included the following sites: C15.0-C26.9; C48.0-48.8; C49.4-49.5; C80.9 and a recorded histology code of 8935 and 8936. This restricted timeframe was imposed to account for changes in the recording of GIST incidence. Individuals with a previous cancer diagnosis or diagnosed post mortem only were excluded. Multiple primary SIRs and 95% confidence intervals (CI) were calculated using SEER*Stat software (V.7.1.0) and compared to general population rates. The SIR was interpreted as an estimate of relative risk (RR). Comparison of characteristics between single and multiple cancer GIST patients was performed using chi-square tests, p-values of <0.05 were considered significant. Results: We identified n=1397 cases of GIST, of which 1291 analyzed. We observed a statistically significant increased incidence of second tumours in patients with a primary GIST (n=78, RR 1.36, 95% CI:1.1-1.7). Older age (p<0.001) and tumor grade (p=0.014) were associated with second primaries, with grade being the only significant variable remaining after logistic regression. In both sexes we observed a significantly increased incidence of kidney cancer (RR 4.3, 95% CI: 1.7-8.9). In females there was a 3 fold higher incidence of colon cancer (RR 2.96 95% CI: 1.2-6.1). Conclusions: Patients with a diagnosis of GIST have a higher incidence of second cancers when compared with standardized incidence in the general population. High grade GISTs were associated with an additional malignancy. Both sexes were observed to have increased incidence of kidney cancer, with females at an increased risk of developing colon cancer. As part of GIST surveillance, screening for colon cancer in females and kidney cancer in both sexes may be considered.