Abstract Purpose To psychometrically evaluate the hypothesized four-factor structure of the 19-item Functional Assessment of Cancer Therapy—Kidney Symptom Index (FKSI-19) health-related quality of life (HRQoL) instrument in a sample of surgically treated renal cell carcinoma (RCC) patients and examine if an alternative factor structure with good psychometric properties may be derived from the available items. Methods The model fit of the hypothesized four-factor structure was examined using confirmatory factor analysis on cohort data from 1731 individuals included in the National Swedish Kidney Cancer Register who had undergone surgery for RCC during the three years 2016–2018 and answered the FKSI-19 instrument within 6–12 months after surgery. Exploratory factor analysis was applied to the same dataset to derive a possible alternative factor solution. Results The four-factor structure did not reach the thresholds for good model fit using the normed χ²-value or the Comparative Fit Index, although the Standardized Root Mean Square Residual and Root Mean Square Error of Approximation measures indicated good and acceptable model fits, respectively. An alternative 14-item trimmed FKSI version (FKSI-14) with a two-factor structure derived from the available FKSI-19 items was found to measure the same aspects of HRQoL as the full FKSI-19 instrument. Conclusion The present study is the first to use psychometric methods for examining the factor structure of the FKSI-19 instrument. The hypothesized four-factor structure of FKSI-19 provided a barely acceptable model fit. The two-factor FKSI-14 structure may be used as an alternative or complement to the four-factor structure when interpreting the FKSI-19 instrument.