This study was carried out in order to outline the human bioclimatic stress/comfort conditions within the area of Iași city, Romania. The meteorological data were obtained over a 7-year period (December 2012–November 2019) from an observation network relying on 8 fixed observation points located in selected spots, relevant for the urban climate conditions in the region. The results demonstrate firstly that throughout the entire analyzed period, using the thermo-hygrometric index (THI), “very cold” conditions characterize 4% of the entire year in the inner parts of the city and 6% in the rural area, while the “hot” THI conditions vary from 18% in the middle of the urban heat island to 15% in the rural area. Overall, the rural areas are generally more comfortable than the inner city, especially during summer, when the urban heat island (UHI) core is starting to develop from the evening and persists during the night. On the contrary, the UHI renders the inner city more comfortable than the rural surroundings from October to April. Similar bioclimatic conditions are also presented in detail for the summer by the relative strain index (RSI), which exceeds the stress threshold value mostly during heat waves, when a significant contrast between urban and rural areas is felt. In brief, it has been determined that the most suitable area for human comfort in Iași city is inside the urban area during the winter and in the rural areas during the summer.