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We present results from the first observations of the Hubble Space Telescope (HST) Panchromatic Comparative Exoplanet Treasury program for WASP-101b, a highly inflated hot Jupiter and one of the community targets proposed for the James Webb Space Telescope (JWST) Early Release Science (ERS) program. From a single HST Wide Field Camera 3 observation, we find that the near-infrared transmission spectrum of WASP-101b contains no significant H2O absorption features and we rule out a clear atmosphere at 13σ. Therefore, WASP-101b is not an optimum target for a JWST ERS program aimed at observing strong molecular transmission features. We compare WASP-101b to the well-studied and nearly identical hot Jupiter WASP-31b. These twin planets show similar temperature–pressure profiles and atmospheric features in the near-infrared. We suggest exoplanets in the same parameter space as WASP-101b and WASP-31b will also exhibit cloudy transmission spectral features. For future HST exoplanet studies, our analysis also suggests that a lower count limit needs to be exceeded per pixel on the detector in order to avoid unwanted instrumental systematics.