The weldability studies of API 5LX80 pipes developed for sour service are very recent and limited information about its heat-affected zone (HAZ) properties can be found. This paper presents a comprehensive evaluation of HAZ using both thermal simulation and the production of actual girth weld joints. The test methodology included microstructural analysis, Charpy impact test, hardness (HV10), microhardness (HV0.1), and sulfide stress cracking tests (SCC). The intercritical coarse grain HAZ presented impact toughness reduction from values above 300 J to less than 50 J at 0 °C when heat input is increased above 1.5 kJ/mm. It can be explained by grain coarsening and martensite-austenite (MA) formation as a ‘necklace’ structure at previous austenite grain boundaries. Hardness and microhardness values for both simulated and actual HAZ were below the maximum limit of 250HV usually specified by industry. Specimens submitted to the sulfide stress cracking (SSC) tests did not present any crack demonstrating that the welded joint is appropriate for sour environments. Finally, a maximum heat input of 1.5 kJ/mm is recommended for field welding. For higher heat inputs, a deeper evaluation of HAZ toughness should be done. The results contribute to supporting the application of this material as an alternative for long-distance high-pressure pipelines with H2S.