Ultrasound (US) is considered the first step in evaluation of patients with shock; respiratory variation of the inferior vena cava (inferior vena cava collapsibility [IVCc]) is an important measurement in this scenario that can be impaired by patient condition or technical skills. The main objective of this study was to evaluate if respiratory variation of the femoral vein (femoral vein collapsibility [FVc]), which is easier to visualize, can adequately predict fluid responsiveness in septic shock patients. Forty-five mechanically ventilated septic shock patients in a mixed clinical-surgical, 30-bed intensive care unit were enrolled in this study. All patients underwent assessments of FVc, IVCc and cardiac output using a portable US device. The passive leg raising test was used to evaluate fluid responsiveness. FVc presented an area under the receiver operating characteristic curve of 0.678 (95% confidence interval: 0.519-0.837, p = 0.044) with a cutoff point of 17%, yielding a sensitivity of 62% and specificity of 65% in predicting fluid responsiveness. IVCc had greater diagnostic accuracy compared with FVc, with an area under the receiver operating characteristic curve of 0.733 (95% confidence interval: 0.563-0.903, p = 0.024) and a cutoff point of 29%, yielding a sensitivity of 47% and specificity of 86%. In conclusion, FVc has moderate accuracy when employed as an indicator of fluid responsiveness in spontaneously mechanically ventilated septic shock patients.